Compositions and methods for the treatment of skin diseases

ABSTRACT

Provided herein are chemical matrices, compositions, methods and devices for the treatment of skin diseases and disorders in an individual. Described herein are non-homogenous chemical matrices and compositions comprising an alcohol selected from ethanol, isopropanol or n-propanol, at least one excipient, and, optionally, at least one pharmaceutical agent, wherein the alcohol is distributed within the chemical matrix as a microbubble. Additionally, methods are described for the use of said chemical matrices and compositions for the treatment of skin diseases and disorders.

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application No.61/612,203, filed Mar. 16, 2012, and U.S. application Ser. No.13/466,860, filed May 8, 2012, the contents of which are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

High ethanol content sanitizer gel is known to be a very effectivetopical antimicrobial agent for preventing infections. Directapplication to bacterial, fungal, and viral organisms in the laboratorysetting results in 99.99% killing within 15 seconds of contact. Thisefficacy is due to its concentration of ethyl alcohol greater than, orequal to, 60% (Federal Register, Vol. 59, No. 116, Jun. 17, 1994).Similar antiseptic activity has been observed for isopropanol (FederalRegister, Vol. 47, No. 99, May 21, 1982). In current commercialformulations, the ethanol containing gel typically contains specialmoisturizers to control dryness on users' hands so they tolerate such ahigh concentration of ethyl alcohol. However, use of these gelscontaining greater than, or equal to, 60% ethyl alcohol on skin damagedwith cracks, tears and/or fissures results in a pronounced stingingsensation (Guideline for Hand Hygiene in Health-care Settings, Centersfor Disease Control,http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5116a1.htm).

SUMMARY OF THE INVENTION

One embodiment disclosed herein provides a means of applying ethanol tothe skin without stinging.

One embodiment provides a chemical matrix comprising from about 2% toabout 30% of an alcohol by volume, a corticosteroid and at least oneexcipient, wherein the chemical matrix is an ointment suitable fortopical administration, the alcohol is primarily dispersed into thechemical matrix in the form of microbubbles, and the alcohol is selectedfrom ethanol, isopropanol, or n-propanol.

Another embodiment provides the chemical matrix wherein the alcohol isethanol. Another embodiment provides the chemical matrix wherein thechemical matrix comprises from about 2% to about 10% ethanol by volume.Another embodiment provides the chemical matrix wherein the chemicalmatrix comprises from about 10% to about 20% ethanol by volume. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 20% to about 30% ethanol by volume.

Another embodiment provides the chemical matrix wherein the ointment isselected from aquaphore, white petrolatum USP, white ointment USP,hydrophilic petrolatum USP, or hydrophilic ointment USP.

Another embodiment provides the chemical matrix wherein thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the corticosteroidcomprises from about 0.1% (w/w) to about 0.0001% (w/w) of the chemicalmatrix. Another embodiment provides the chemical matrix wherein thechemical matrix comprises from about 2% to about 10% ethanol by volumeand the corticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 10% to about 20% ethanol by volume and thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 20% to about 30% ethanol by volume and thecorticosteroid is selected from desonide, or mometasone.

Another embodiment provides the chemical matrix wherein the chemicalmatrix comprises from about 2% to about 10% ethanol by volume, thecorticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix. Another embodiment provides the chemical matrixwherein the chemical matrix comprises from about 10% to about 20%ethanol by volume, the corticosteroid is selected from desonide, ormometasone, and the corticosteroid comprises from about 0.1% (w/w) toabout 0.0001% (w/w) of the chemical matrix. Another embodiment providesthe chemical matrix wherein the chemical matrix comprises from about 20%to about 30% ethanol by volume, the corticosteroid is selected fromdesonide, or mometasone, and the corticosteroid comprises from about0.1% (w/w) to about 0.0001% (w/w) of the chemical matrix.

One embodiment provides a method of treating a skin disease or disorderin an individual in need thereof comprising topical application to theindividual of a chemical matrix comprising from about 2% to about 30% ofan alcohol by volume, a corticosteroid and at least one excipient,wherein the chemical matrix is an ointment suitable for topicaladministration, the alcohol is primarily dispersed into the chemicalmatrix in the form of microbubbles, and the alcohol is selected fromethanol, isopropanol, or n-propanol.

Another embodiment provides the method wherein the alcohol is ethanol.Another embodiment provides the method wherein the chemical matrixcomprises from about 2% to about 10% ethanol by volume. Anotherembodiment provides the method wherein the chemical matrix comprisesfrom about 10% to about 20% ethanol by volume. Another embodimentprovides the method wherein the chemical matrix comprises from about 20%to about 30% ethanol by volume. Another embodiment provides the methodwherein the ointment is selected from aquaphore, white petrolatum USP,white ointment USP, hydrophilic petrolatum USP, or hydrophilic ointmentUSP. Another embodiment provides the method wherein the corticosteroidis selected from desonide, or mometasone. Another embodiment providesthe method wherein the corticosteroid comprises from about 0.1% (w/w) toabout 0.0001% (w/w) of the chemical matrix. Another embodiment providesthe method wherein the chemical matrix comprises from about 2% to about10% ethanol by volume and the corticosteroid is selected from desonide,or mometasone. Another embodiment provides the method wherein thechemical matrix comprises from about 10% to about 20% ethanol by volumeand the corticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the method wherein the chemical matrix comprisesfrom about 20% to about 30% ethanol by volume and the corticosteroid isselected from desonide, or mometasone.

Another embodiment provides the method wherein the chemical matrixcomprises from about 2% to about 10% ethanol by volume, thecorticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix. Another embodiment provides the method wherein thechemical matrix comprises from about 10% to about 20% ethanol by volume,the corticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix. Another embodiment provides the method wherein thechemical matrix comprises from about 20% to about 30% ethanol by volume,the corticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix.

Another embodiment provides the method wherein the skin disease ordisorder is dermatitis. Another embodiment provides the method whereinthe skin disease or disorder is eczema. Another embodiment provides themethod wherein the skin disease or disorder is atopic dermatitis.

DETAILED DESCRIPTION OF THE INVENTION

New treatments are needed for many dermatologic diseases because currenttreatments lack efficacy, exhibit side effects, or are so unpleasant touse that patients are discouraged from using them. In a series ofclinical trials it has been found that, in comparison to currenttreatments, use of the compositions described herein produces clinicaloutcomes characterized by equal or higher efficacy, while exhibitingminimal side effects and good patient compliance.

It has been discovered that certain topical compositions (lotions,creams, ointments, emulsions and dispersions) that contain ethanol orcertain other alcohols distributed non-homogenously have the unexpectedbenefit of effectively treating a variety of dermatologic diseases anddisorders. Whereas previously known only for maintaining hygiene onhealthy skin, now it is possible to use topical compositions containingethanol or certain other alcohols to treat diseases and disorders of theskin wherein the skin is damaged, broken, torn, or marked by fissures.These skin diseases and disorders range from infections (bacterial orfungal) to inflammatory diseases (dermatitis, psoriasis, acne vulgaris,or rosacea). It has been also discovered that the topical compositionsdescribed herein can be safely used on the face. Effective treatmentscan be achieved, in some cases, through use of the topical compositionsdescribed herein wherein ethanol or another alcohol is the sole activeingredient. Further advantages can be obtained by incorporating intosaid compositions at least one additional therapeutic active agent. Onedistinguishing feature of these compositions is the non-homogenousnature of the formulation. In particular, it has been found that whenthe ethanol or other alcohol is distributed in a non-homogenous fashionthroughout the composition into bubble-like regions of locally highconcentration, where the approximate effective concentration of theethanol or other alcohol in the bubble-like regions is about 60% toabout 80%, a beneficial effect is observed upon topical application todamaged skin but without a stinging sensation. This result is strikingwhen compared to the well-known stinging sensation observed uponapplication of commercially available high ethanol content sanitizersgels to damaged skin.

DEFINITIONS

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

The term “noncomedogenic” describes the tendency of some dermatologicalproducts, such as oils, lotions, ointments, creams, and gels to blockthe pores of the skin. Noncomedogenic products are less likely to clogpores and lead to formation of blackheads (open comedones), whiteheads(closed comedones), red bumps (inflammatory papules) and red, swollen,pussy red bumps and lumps (inflammatory pustules, nodules, and cysts) inpatients' skin. Comedogenic ingredients of many commercially availableskin care products include isopropyl myristate, cocoa butter, coconutoils, and wheat germ oil.

The term “subjective irritation” describes burning, stinging, or itchingwithout detectable visible or microscopic changes in the skin.

The term “non-homogeneous” describes the lack of a uniform phasethroughout the bulk, or entirety, of the composition. The terms“non-homogeneous” and “heterogeneous” are synonymous and can be usedinterchangeably. As used herein, the terms “non-homogeneous” and“heterogeneous” refer to the bulk, or entirety, of the composition asemployed by the patient or caregiver.

The term “semisolid” describes a material that has the properties of asolid and of a liquid.

The term “gel” describes a semisolid dosage form that contains a gellingagent to provide stiffness to a solution or colloidal dispersion (US FDADrug Nomenclature Monograph, number C-DRG-00201). A gel may containsuspended particles. A gel can contain >50% water and other volatiles(Buhse L, et. al. International Journal of Pharmaceutics; 295: 101-112).A gel offers nongreasy medication delivery.

The term “oil” describes an unctuous, combustible substance which isliquid, or easily liquefiable, on warming, and is soluble in ether butinsoluble in water. Oils are classified as animal, mineral or vegetableoils, depending on their origin (US FDA Drug Nomenclature Monograph,number C-DRG-00201).

The term “emulsion” describes a dosage form consisting of a two-phasesystem comprised of at least two immiscible liquids, one of which isdispersed as droplets (internal or dispersed phase) within the otherliquid (external or continuous phase) generally stabilized with one ormore emulsifying agents (US FDA Drug Nomenclature Monograph, numberC-DRG-00201).

The term “lotion” describes an emulsion liquid dosage form. This dosageform is generally for external application to the skin (US FDA DrugNomenclature Monograph, number C-DRG-00201). A lotion may containmoisturizing agents which can help increase skin moisture. A lotion maycontain small amounts of alcoholic preservatives to prevent microbialgrowth during product life.

The term “cream” describes an emulsion semisolid dosage form, usuallycontaining >20% water and volatiles and/or <50% hydrocarbons, waxes orpolyols as the vehicle. A cream is more viscous than a lotion. Thisdosage form is generally for external application to the skin or mucousmembranes (US FDA Drug Nomenclature Monograph, number C-DRG-00201). Acream may contain moisturizing agents which can help increase skinmoisture. A cream may contain alcoholic preservatives to preventmicrobial growth during product life.

The term “ointment” describes a semisolid dosage form, usuallycontaining <20% water and volatiles and/or >50% hydrocarbons, waxes orpolyols as the vehicle. This dosage form is generally for externalapplication to the skin or mucous membranes (US FDA Drug NomenclatureMonograph, number C-DRG-00201). An ointment offers a dense, occlusivecovering which increases hydration of dry skin rashes.

The term “solution” describes a clear, homogeneous liquid dosage formthat contains one or more chemical substances dissolved in a solvent ormixture of mutually miscible solvents (US FDA Drug NomenclatureMonograph, number C-DRG-00201).

The term “high ethanol content” describes a composition comprisingthroughout the bulk or entirety of the composition, greater than orequal to 60% ethyl alcohol content. Commercially available handsanitizer gels are one example of a high ethanol content composition(Federal Register, Vol. 59, No. 116, Jun. 17, 1994).

Skin Diseases and Disorders

Acne Vulgaris (“Teenage Acne”)

Acne is a common skin disease that affects 60-70% of Americans at sometime during their lives(http://emedicine.medscape.com/article/1069804-overview). Teenagers mayneed ongoing treatment from age 12 to 23 years old.

Acne vulgaris is characterized by the onset around puberty of comedonesand inflammatory lesions on the face, neck, chest, and back. It tends toresolve on average around age 23 years of age. The pathogenesis ismultifactorial. There is increased oil production by increasingly activeskin oil glands under the influence of puberty associated hormones. Anobstruction of the secretory tubules (“pores”) which connect the glandto the skin surface leads to accumulation of oil under the skin surface.As the volume increases the lumps called comedones become visible.Bacteria then proliferate in the oil leading to further inflammation inthe skin causing the formation of the visible red papules, pustules,nodules, and cysts typically seen in acne vulgaris. The specificbacteria infecting these lesions has been identified asProprionobacterium acnes. These lesions can be uncomfortable or tender,can create disfigurement of the teenager compared to his peers, leadingto embarrassment in affected boys and girls. Thus teenagers frequentlyseek treatment to minimize this disorder.

Treatment is based on agents which seek to correct the fundamentalpathologic events creating acne lesions.

Topical treatments fall into several classes:

a) “Comedolytic agents” dissolve the secretory tubule obstruction thusallowing drainage of the trapped oil. Topical agents of this typeinclude: sulfur, resorcinol, salicyclic acid, glycolic acid, retinoidssuch as tretinoin, adapaline and tazarotene, and benzoyl peroxide.

b) “Antibacterial agents” suppress the bacterial population. Topicalagents of this class include: benzoyl peroxide, antibiotics(erythromycin, clindamycin), and astringents, and nonspecific mechanismagents like azelaic acid.

c) “Cleansers” seek to dissolve surface oil, dissolve clogged pores, andremove bacteria. Oral treatments: These include oral antibiotics(tetracycline family, erythromycin macrolide family, ampicillinpenicillin family) which suppress the bacteria. The oral agent13-cis-retinoic acid (Accutane™) seeks to reduce oil production andresolve clogging of the pores.

In some embodiments, the compositions and methods described herein areuseful for the treatment of acne vulgaris. In some embodiments, thecompositions and methods described herein are an excellent first linetreatment for mild to moderate, and some cases, severe pustular acneseen in teenagers. The compositions and methods described herein can beused independently, or in combination with over-the-counter and/orprescription dispensed therapeutically active agents to address alltypes of acne lesions. In some embodiments, the compositions disclosedherein include at least one comedolytic agent. In some embodiments, thecompositions disclosed herein include at least one anti-inflammatoryagent. In some embodiments, the compositions disclosed herein include atleast one antibiotic agent.

Rosacea (“Adult Acne”)

In this disorder, adults, usually 25 years and older, develop a triad ofdistinctive features separating it from acne vulgaris (“teenage acne”).The triad consists of:

a) central facial increased redness and increased surface blood vessels;

b) central facial inflammatory red papules, pustules, and nodules;

c) tendency to easy facial flushing and blushing in response to triggerfactors including certain psychological states (embarrassment or anger),exercise during workouts, consumption of alcoholic drinks and hotcoffee/tea.

The condition can last for many years and gradually worsen. Patients areusually motivated to seek treatment because of the disfigurement of theskin disorder.

In a recent study, Dr. Maeve McAleer and colleagues at the School ofPublic Health and Population Science, University College, Dublin, foundthat 14.4 percent of 1,000 subjects examined in Ireland had rosacea.Moreover, in a 1989 study of 800 office workers in Sweden, theprevalence of rosacea was 10 percent—including 14 percent in women and 6percent in men(http://www.rosacea.org/weblog/2010/04/01/rosacea_incidence_on_rise/index.php).

The specific pathogenesis of rosacea is not known. The same bacteriafound infecting acne vulgaris lesions has not been found in rosacea.There are no plugged up pores (comedones) present in rosacea patients.There are many hypotheses for rosacea causation revolving around apostulated bacteria which infects the skin leading to the inflammationso characteristic of the condition.

Treatment of rosacea involves the use of topical and oral agents.

Topical Agents:

a) Antimicrobial agents: metronidazole, sulfa/sulfur combinations,clindamycin, benzoyl peroxide;

b) Anti-inflammatory agents of uncertain mechanism: azelaic acid.

Oral Agents:

a) Antibacterial agents: These include oral antibiotics (tetracyclinefamily, erythromycin macrolide family, ampicillin penicillin family)which suppress growth of bacteria and/or kill bacteria.

Use of the compositions and methods described herein is a very effectivetopical treatment for red bumps and pussy bumps of rosacea. Thetreatment produces clinical improvement noticeable to the patientswithin a week of starting treatment. Of equal significance is that thistreatment rapidly reduces central facial redness. This is not true oftopical Finacea™ or Metrogel™ which are the current standard of care forthis indication. Advantages of the compositions and methods disclosedherein for the treatment of rosacea over current topical treatments,such as Finacea and Metrogel, include faster onset of relief, reliablyreduces redness, no stinging, less costly, and reduced environmentalimpact. Advantages of the compositions and methods disclosed herein forthe treatment of rosacea over current oral include no concerns aboutsafety of oral antibiotics, no upset stomach or sun sensitizationissues, no impact on use of oral contraceptives, no issue of vaginalyeast infections, and reduced environmental impact. In some embodiments,the compositions and methods described herein are useful for thetreatment of rosacea. In some embodiments the compositions disclosedherein include at least one anti-inflammatory agent. In someembodiments, the compositions disclosed herein include at least oneantibiotic agent.

Dermatitis

Dermatitis, or eczema, is a common, very uncomfortable, frequently veryitchy, rash characterized by red, scaly, patches in the skin. Theredness, swelling, and discharge are all signs of inflammation of anallergic type process. The classification of the dermatitis isdetermined by the appearance and distribution of the patches and thedemographics of the patient. For example, atopic dermatitis ischaracterized by rash patches located typically in the fronts of theelbows and behind the knees in young children. Nummular dermatitis ischaracterized by round rash patches scattered randomly on the trunk andlimbs of adults. Contact dermatitis is characterized by linear shapedswollen patches on the trunk or limbs at any age.

Prior to the discovery of the methods, compositions and devicesdisclosed herein, the use of high ethanol content gels in the treatmentof eczema was complicated by a stinging sensation upon topicalapplication. This stinging occurs because the acute phase of the rash ischaracterized by many small cracks and fissures in the skin. By usingthe methods, compositions and devices disclosed herein to treat theacute phase of eczematous lesions topical application of the compositiondoes not cause a stinging sensation. Maintenance therapy employing themethods, compositions and devices disclosed herein to suppress therecurrence of eczematous lesions is provided by application of thecomposition, such that topical application of the composition does notcause a stinging sensation.

During the sub-acute phase (rash but no fissures) the compositiondisclosed herein is well tolerated and can greatly increase efficacy ofconcomitant or subsequent topical steroid therapy in resolving theremaining rash. Once the eczema is resolved, ongoing use of thecompositions as disclosed herein that do not contain corticosteroid canhelp sustain the disease-free remission period. The addition ofmoisturizing ingredients to the compositions disclosed herein can keepthe skin moist.

In some embodiments, the compositions and methods described herein areuseful for the treatment of dermatitis. In some embodiments thecompositions disclosed herein include at least one anti-inflammatoryagent.

Atopic Dermatitis

Atopic dermatitis occurs in approximately 10-20% of children and 2% ofadults (Ong P Y, Leung D Y. Immune dysregulation in atopic dermatitis.Curr Allergy Asthma Rep. September 2006; 6(5):384-9).

In the developed countries of North America and Europe, children fromages 2 to 8 years commonly suffer from this itching, unattractive rash.The discomfort and sleep deprivation are a major burden for patients andtheir families.

Treatment of eczema is difficult and often requires a multi-facetedapproach. Moisturizers are administered to relieve dry skin. Coldcompresses can relieve itch. Corticosteroid and topical calcineurininhibitors can reduce inflammation. Antibiotics treat bacterialinfection. Sedative antihistamines can enable sleep and rest. Formoderate to severe cases, phototherapy can be used.

The latest scientific understanding of the causes of eczema highlightthe unmet medical need satisfied by the methods, compositions anddevices disclosed herein. In patients with eczema, the skin is drierthan usual with outer layer cracks and fissures which facilitate easycolonization by a particular bacterium, Staphylococcus aureus(Boguniewicz M, Leung D Y M. Atopic dermatitis: a disease of alteredskin barrier and immune dysregulation. Immunolog Rev. 2011; 24:233-46).The staphylococcal population density in the skin rises greatly becausethe patients are deficient in some of the usual factors required todefend against them (Miajlovic H, Fallon P G, Irvine A D, Foster T J.Effect of filaggrin breakdown products on growth of and proteinexpression by Staphylococcus aureus. J. Allergy Clin. Immunol. 2010;126:1184-1190; Cho S-H, Strickland I, Boguniewicz M, et. al. Fibronectinand fibrinogen contributes to the enhanced binding of S. aureus toatopic skin. J. Allergy Clin. Immunol. 2001; 108:269-74; Bunikowski R,Mielke M, Skarabis H, et al. Prevalence and role of serum IgE antibodiesto the Staphylococcus aureus-derived superantigens SEA and SEB inchildren with atopic dermatitis. J. Allergy Clin. Immunol. 1999;103:119-24; Leung D Y M, Harbeck R, Bina P, et al. Presence of IgEantibodies to staphylococcal exotoxins on the skin of patients withatopic dermatitis: evidence for a new group of allergens. J. Clin.Invest. 1993; 92:1374-80; Zollner T M, Wichelhaus T A, Hartung A, et al.Colonization with superantigen-producing Staphylococcus aureus isassociated with increased severity of atopic dermatitis. Clin. Exp.Allergy 2000; 30: 994-1000). The staphylococci worsen the eczema by animmune mechanism which up-regulates inflammation culminating in thesymptoms and appearance of the visible eczema rash (Reginald K,Westritschnig K, Linhard B, Focke-Tejkl M, et. al. Staphylococcus aureusfibronectin-binding protein specifically binds IgE from patients withatopic dermatitis and requires antigen presentation for cellular immuneresponses. J. Allergy Clin. Immunol. 2011; 128:82-91).

Measures which decrease this bacterial population are generally found tohelp resolve eczema. Oral and topical antibiotics currently are used forthis purpose. Previously, high ethanol content gels were to be avoideddue to the stinging sensation upon topical application as the stingingsensation would lead to a lack of patient compliance.

While the use of “bleach baths” has recently been shown to improveeczema by lowering the S. aureus skin population (Huang J T, Abrams M,Tlougan B, Rademaker A, Paller A S. Treatment of staphylococcus aureuscolonization in atopic dermatitis decreases disease severity. PediatricsMay 2009; 123(5): 808-814) caregivers are reluctant to use thistreatment because of the time and effort required. This effort includespreparing the bath, cleaning up afterwards, ventilating the bathroom toremove the bleach odor, and trying to avoid bleaching bathroom linens.

Use of the compositions as described herein is a significant advance fortopical therapy in eczema. Caregivers find applying the compositionsdescribed herein to be an easy and familiar way of treating skinproblems. The caregiver applies a single composition that contains asecondary topical medication. This single composition is formulated tocause no irritation to the skin, such as a stinging sensation. Preferreddosage forms of this composition include non-homogenous ointments,lotions, creams and other emulsions or dispersions where the ethanol canbe suspended or dispersed in the non-aqueous component to avoid astinging sensation upon topical application. In some embodiments, thecompositions and methods described herein are useful for the treatmentof atopic dermatitis. In some embodiments the compositions disclosedherein include at least one anti-inflammatory agent. In some embodimentsthe compositions disclosed herein include at least one corticosteroid.

Contact Dermatitis

Irritant contact dermatitis can occur after brief exposure to a strongirritant or frequent exposure to a mild irritant. When contact with theirritant damages the skin faster than the skin can repair itself,irritant contact dermatitis can develop.

Allergic contact dermatitis usually develops within hours after theallergen makes skin contact. Nearly 3000 allergens are known to causeallergic contact dermatitis. Common allergens include fragrances,metals, plants, clothing and shoes.

Current treatments include avoidance of the irritant or allergen,frequent use of topical moisturizers, application of topicalcorticosteroid to reduce inflammation and administration of antibioticsshould an infection develop. Phototherapy can be used in severe cases tosuppress the overactive immune response.

In some embodiments, the compositions and methods described herein areuseful for the treatment of contact dermatitis.

Dyshidrotic Dermatitis (Hand Eczema)

Dyshidrotic dermatitis, also known as hand eczema, pompholyx, vesiculareczema, or vesicular palmoplantar eczema, occurs only on the palms ofthe hands, sides of fingers and soles of the feet. It typically causes aburning, itching sensation and a blistering rash.

Patients with dyshidrotic dermatitis are typically between 20 and 40years of age. Risk factors include stress and pre-existing conditions(atopic condition, contact dermatitis, infection).

Current treatments include the use of topical corticosteroid and coldcompresses, antibiotics, topical medications to relieve pain and itch,and topical calcineurin inhibitors to reduce inflammation as well asdrainage of large blisters to relieve pain.

In some embodiments, the compositions and methods described herein areuseful for the treatment of dyshidrotic dermatitis.

Seborrheic Dermatitis (Seborrheic Eczema)

Seborrheic dermatitis, also known as cradle cap, seborrhea, or dandruff,usually begins on the scalp as oily, waxy patches and can sometimesspread to the face and beyond. Symptoms can also include flaking skin;reddish, somewhat swollen skin; and constant itchiness. In some cases,seborrheic dermatitis is thought to be triggered by the microorganismmalassezia.

Current treatments include administration of a topical mildcorticosteroid and topical anti-fungal medication, such as ketoconazole,as well as the use of a specific shampoo regimen.

In some embodiments, the compositions and methods described herein areuseful for the treatment of seborrheic dermatitis.

Nummular Dermatitis (Eczema)

Nummular dermatitis presents itself as unique, coin-shaped or ovallesions.

Approximately 2 out of every 1000 people in the United States developnummular eczema. Men develop it more frequently, with the first incidentoccurring between 55 and 65 years of age. Women tend to develop nummulardermatitis between 15 and 25 years of age.

Current treatments include methods to hydrate the skin (use of ahumidifier, use of moisturizers) and the use of topical and/or oralmedications (corticosteroids, antibiotics, antihistamine).

In some embodiments, the compositions and methods described herein areuseful for the treatment of nummular dermatitis.

Neurodermatitis (Eczema)

Neurodermatitis develops when nerve endings in the skin becomeirritated, triggering a severe itch-scratch-itch cycle. Common causes ofnerve irritation include an insect bite and emotional stress.

Neurodermatitis occurs more frequently in people who have psoriasis orcontact dermatitis, people who have an atopic condition (atopicdermatitis, hayfever, asthma), females, and people between 30 and 50years of age.

Current treatments include administration of a topical corticosteroid, atopical or oral antibiotic, a topical keratolytic, and asedative/tranquilizer.

In some embodiments, the compositions and methods described herein areuseful for the treatment of neurodermatitis.

Stasis Dermatitis (Eczema)

Stasis dermatitis, also known as gravitational dermatitis, venousdermatitis, or venous stasis dermatitis, develops in the lower legs whencirculation becomes sluggish. Poor blood flow leads to fluid build-up.The legs swell, causing the development of a rash that usually itches,painful sores and discolored thinning skin.

In the United States, about 15-20 million people over 50 years of agehave stasis dermatitis.

Current treatments include methods to increase blood flow in the legs aswell as the administration of topical and/or oral medications(corticosteroids, antibiotics).

In some embodiments, the compositions and methods described herein areuseful for the treatment of stasis dermatitis.

Hand Dermatitis (Eczema)

Hand dermatitis is not one specific type of eczema but rather any typeof eczema that develops on the hands.

Estimates indicate that between 2% and 10% of Americans have some formof hand dermatitis. Hand dermatitis may account for 80% of alljob-related skin conditions. People in occupations that involve frequenthand immersion in water are more susceptible to the development of handdermatitis.

Current treatments include administration of topical or oralcorticosteroids and/or antibiotics, topical tars, and topicalcalcineurin inhibitors as well as the use of phototherapy or botulinumtoxin type A injections.

In some embodiments, the compositions and methods described herein areuseful for the treatment of hand dermatitis.

Occupational Dermatitis (Eczema)

Occupational dermatitis is not one specific type of eczema but ratherany type of eczema that is caused by a person's workplace.

Estimates indicate that 5% of men and 10% of women in the workforcedevelop eczema on their hands from workplace exposure. Often, the eczemais the result of an irritant (irritant contact dermatitis) or anallergic reaction (allergic contact dermatitis). Occupational dermatitiscan also occur on the face and forearms.

Current treatments include avoidance of the irritant/allergen, frequentuse of topical moisturizers, application of topical corticosteroid toreduce inflammation and administration of antibiotics should aninfection develop. Phototherapy can be used in severe cases to suppressthe overactive immune response.

In some embodiments, the compositions and methods described herein areuseful for the treatment of occupational dermatitis.

Secondarily Infected Dermatitis

Due to the marked itchiness of rashes, dermatitis patients frequentlyscratch the affected skin disrupting its integrity and providing a“portal of entry” for bacteria to infect the skin. Thus a rash whichbegan with only inflammation soon becomes so called “secondarily”infected with bacteria. This colonization of the rash with an overgrowthof abnormal bacteria (often Staphylococcus aureus) further contributesto skin irritation. Thus, because a secondary infection has occurred,effective treatment of the rash must suppress both inflammation andinfection.

Treatment of dermatitis employs several classes of therapeutic agents.

Topical Treatment:

a) Immunosuppressive agents to reduce inflammation includecorticosteroids such as hydrocortisone and many other related molecules,and immunomodulating agents such as tacrolimus and pimecrolimus.

b) Antibacterial agents to suppress bacterial infection includemupirocin, retapamulin, neomycin, bacitractin, polymyxin, and sulfa.

Oral Treatment:

a) Immunosuppressive agents to reduce inflammation includecorticosteroids like prednisone

b) Antibiotics to suppress bacterial infection include tetracyclinefamily, erythromycin macrolide family, penicillin family, cephalosporinfamily, ciprofloxacin family, and clindamycin.

c) oral antihistamines to reduce the itch and swelling of inflammation.

Use of compositions as described herein dramatically improves theefficacy of topical steroids while eliminating the need for topical andoral antibiotics. This simpler treatment means better compliance andbetter success in treatment.

In some embodiments, the compositions and methods described herein areuseful for the treatment of secondarily infected dermatitis. In someembodiments, the compositions disclosed herein include at least oneimmunosuppressive agent. In some embodiments, the compositions disclosedherein include at least one antimicrobial agent.

Pitted Keratolysis

Pitted keratolysis is a distinctive non-inflammatory bacterial infectionof the soles of the feet that is characterized by appearance of pits onthe soles. It usually occurs in teenagers and young adults with sweatsoaked skin due to athletic activities and not changing to dry socks.This wet condition leads to maceration and breakdown of the outer skinlayer creating a portal of entry for a specific bacteria: Erythromycesminitussitum. It is foul smelling and gives a “swiss cheese” appearanceto the soles of the feet.

Current standard of treatment includes topical application of agents todecrease sweating to dry the feet (aluminum chloride) and antibacterialagents to suppress the bacterial infection (erythromycin, orclindamycin).

In some embodiments, the compositions and methods described herein areuseful for the treatment of pitted keratolysis.

Athlete's Foot (Tinea Pedis)

Tinea pedis is thought to be the world's most common dermatophytosis.Reportedly, 70% of the population will be infected with tinea pedis atsome time(http://emedicine.medscape.com/article/1091684-overview#a0199).

In this fungal infection of the soles, there are dry pink to tan scalypatches which gradually expand to cover the sole and the web spacesbetween the toes. Often cracks occur due to the dryness causingdecreased skin flexibility. Symptoms often range from mild to severeitching from the inflammation of the skin and mild to severe discomfortdue to the cracks. Typically it begins in teen years and can lastthrough adulthood. Sometimes painful blisters can occur due to theintense inflammation induced by the immune defense response to thefungal infection.

Current standard of treatment includes administration of topical agentsand/or the use of oral agents. Topical treatment include antifungalagents such as terbenafine, econazole, miconazole, clotrimazole,butenafine, tolnaftate, or salicylic acid. All of these agents typicallytake 2-4 weeks to improve the rash. Oral agents used for the treatmentof tinea pedis include griseofulvin, terbenafine, itraconazole, orfluconazole. While effective, these pose risks of toxicity includingblood, liver, and heart injury.

In some embodiments, the compositions and methods described herein areuseful for the treatment of tinea pedis. In some embodiments thecompositions disclosed herein include at least one anti-fungal agent.

Tinea Versicolor

Tinea versicolor is a chronic fungal infection of the skin and ischaracterized as a rash in humans known to be caused by pitryosporum andtwo species of malassezia genus yeast: malassezia globosa and malasseziafurfur (Crespo-Erchiga V, Florencio V D. Malassezia yeasts andpityriasis versicolor. Curr Opin Infect Dis. April 2006; 19(2):139-47;Gaitanis G, Velegraki A, Alexopoulos E C, Chasapi V, Tsigonia A,Katsambas A. Distribution of Malassezia species in pityriasis versicolorand seborrhoeic dermatitis in Greece. Typing of the major pityriasisversicolor isolate M. globosa. Br J Dermatol. May 2006; 154(5):854-9;Morishita N, Sei Y, Sugita T. Molecular analysis of malasseziamicroflora from patients with pityriasis versicolor. Mycopathologia.February 2006; 161(2):61-5; Rincon S, Celis A, Sopo L, Motta A, Ceperode Garcia M C. Malassezia yeast species isolated from patients withdermatologic lesions. Biomedica. June 2005; 25(2):189-95; Krisanty R I,Bramono K, Made Wisnu I. Identification of Malassezia species frompityriasis versicolor in Indonesia and its relationship with clinicalcharacteristics. Mycoses. May 2009; 52(3):257-62). Treatment consists ofapplying antifungal medicines to the skin. These medications includeclotrimazole, ketoconazole, and miconazole.

In some embodiments, the compositions and methods described herein areuseful for the treatment of tinea versicolor. In some embodiments, themethods described herein are useful for the treatment of tineaversicolor. In some embodiments, the compositions disclosed hereininclude at least one anti-fungal agent.

Psoriasis

According to the National Institutes of Health (NIH), approximately 2.2%of the United States population have psoriasis(http://emedicine.medscape.com/article/1943419-overview#a0156).Psoriasis is characterized by red scaly elevated plaques which are oftenlocated on elbows and knees but can be extensively spread out on theskin of the trunk, limbs, and scalp. This is a chronic, often recurrent,condition which usually begins in early adulthood and lasts thelifetime. Sometimes children are affected. The rash can beuncomfortable, unsightly, and embarrassing.

The pathogenesis of psoriasis is not well understood. Currentunderstanding suggests immune system activation leading to inflammatorychanges in the skin. Current methods of treatment seek to reverse theinflammatory changes and reduce the overgrowth thickening of theaffected skin areas.

Topical treatment includes use of anti-inflammatory agents (such ascorticosteroids to reduce the inflammation in the skin) andantiproliferative agents (such as calcipotriene to reduce the skinovergrowth). Topical agents often have limited effectiveness due toinadequate percutaneous drug delivery through the thickened psoriaticskin. To overcome this obstacle, a topical agent can be covered overwith an air impermeable plastic sheet (Saran Wrap™) to increasepercutaneous drug delivery. While effective, it is very uncomfortable towear leading to poor compliance and thus inadequate efficacy.

Oral or systemic agents include anti-inflammatory agents (such asmethotrexate, or cyclosporine), and tumor necrosis factor inhibitors(etenercept, infliximab, and similar others). While effective they candamage blood and liver and pose risks of severe toxicity includingdeath. Other modes of therapy include ultraviolet light treatment tosuppress epidermal growth (however, one drawback of this treatment isthe potential to cause cancer of the skin) and corticosteroid injectionsinto patch suppresses inflammation locally (this is very uncomfortableand can lead to unsightly thinning where injected).

In some embodiments, the compositions and methods described herein areuseful for the treatment of psoriasis. In some embodiments thecompositions disclosed herein include at least one anti-inflammatoryagent. In some embodiments the compositions disclosed herein include atleast one anti-proliferative agent.

Test for Stinging

An assessment of stinging can be made using a superficial skin abrasionmodel. When the skin is disrupted by superficial wounds, subsequentlyapplied materials can sting, burn, and irritate. To measure thestinging, standardized wounds can be created in the skin, typically onthe forearm, by sequential tape stripping repeated until the glisteninglayer is reached. This glistening layer corresponds to the skin's dermallayer where nerves are located. Materials to be tested on thesuperficial wounds would include a positive control material, such 70%ethanol solution, a negative control, such as the formulation vehiclewithout active agents, and the test formulation(s). Each material isapplied to a single site on the abraded forearm for a short duration oftime, such as 15 seconds. The study subject is then asked to rate theintensity of stinging/burning using a predesignated multi-point scale.Thus, stinging as well as burning sensations can be assessed by thismethod.

For example, in a study of novel first aid formulation for wounds,standardized wounds were created by sequential tape stripping repeateduntil the glistening layer was reached (Pagnoni A, Spinelli G, Berger RS, Bowman J, Garreffa S, Snoddy A M. Lack of burning and stinging from anovel first aid formulation applied to experimental wounds. J. Cosmet.Sci. March-April 2004; 55(2):157-62). Each material to be tested wasapplied to a wound for 15 seconds. The 24 subjects in the study reportedthe intensity of the stinging/burning sensation. The tested materialsincluded 70% isopropyl alcohol (sting/burn control), sterile 0.9% sodiumchloride solution (no sting/no burn control) and the novel formulation.It was found that the alcohol stung while the novel formulation stung nomore than the saline solution.

In another example, irritation of superficial wounds by topical agentscommonly used in wound care was assessed using this superficial skinabrasion model (Trookman N S, Rizer R L, Weber T. J. Amer. Acad.Dermatol. March 2011; 64(3), Suppl 1:S16-22). As in the previousexample, the skin was prepared by sequential tape stripping prior totopical application of the materials in the study.

Methods of Treatment

One embodiment provides a method of treating a skin disease or disorderin an individual comprising topical application to the skin of a subjectin need thereof of a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% of analcohol by volume and at least one excipient wherein said composition isa non-homogeneous semisolid and the alcohol is selected from ethanol,isopropanol, or n-propanol. One embodiment provides a method of treatinga skin disease or disorder in an individual comprising topicalapplication of a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% ethanol byvolume, and at least one excipient wherein the composition is anon-homogeneous semisolid. Another embodiment provides the methodwherein the composition is a non-homogenous semisolid dispersion. Oneembodiment provides a method of treating a skin disease or disorder inan individual comprising topical application to the skin of a subject inneed thereof of a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% of analcohol by volume and at least one excipient wherein said composition isa non-homogeneous emulsion and the alcohol is selected from ethanol,isopropanol, or n-propanol. Another embodiment provides the methodwherein the composition is a non-homogenous semisolid emulsion. Anotherembodiment provides the method wherein the composition is anon-homogenous cream or a non-homogenous ointment. Another embodimentprovides the method wherein the composition is a non-homogenous cream.Another embodiment provides the method wherein the composition is anon-homogenous ointment. Another embodiment provides the method whereinthe composition is a non-homogeneous emulsion. Another embodimentprovides the method wherein the composition is a non-homogenousdispersion. Another embodiment provides the method wherein thecomposition is a non-homogenous cream or a non-homogenous lotion.Another embodiment provides the method wherein the composition is anon-homogenous lotion.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% ethanol by volume, and atleast one excipient wherein the composition is a non-homogeneoussemisolid and the method is for maintenance therapy. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid dispersion. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid emulsion. Another embodimentprovides the method wherein the composition is a non-homogenous cream ora non-homogenous ointment. Another embodiment provides the methodwherein the composition is a non-homogenous cream. Another embodimentprovides the method wherein the composition is a non-homogenousointment. Another embodiment provides the method wherein the compositionis a non-homogeneous emulsion. Another embodiment provides the methodwherein the composition is a non-homogenous dispersion. Anotherembodiment provides the method wherein the composition is anon-homogenous cream or a non-homogenous lotion. Another embodimentprovides the method wherein the composition is a non-homogenous lotion.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% ethanol by volume, and atleast one excipient wherein the composition is a non-homogeneoussemisolid and the method is for preventive treatment of the skin diseaseor disorder. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid dispersion. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid emulsion. Another embodiment provides the method wherein thecomposition is a non-homogenous cream or a non-homogenous ointment.Another embodiment provides the method wherein the composition is anon-homogenous cream. Another embodiment provides the method wherein thecomposition is a non-homogenous ointment. Another embodiment providesthe method wherein the composition is a non-homogeneous emulsion.Another embodiment provides the method wherein the composition is anon-homogenous dispersion. Another embodiment provides the methodwherein the composition is a non-homogenous cream or a non-homogenouslotion. Another embodiment provides the method wherein the compositionis a non-homogenous lotion.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% ethanol by volume, and atleast one excipient wherein the composition is a non-homogeneoussemisolid and the method is for prophylactic treatment of the skindisease or disorder. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid dispersion. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid emulsion. Another embodiment provides the method wherein thecomposition is a non-homogenous cream or a non-homogenous ointment.Another embodiment provides the method wherein the composition is anon-homogenous cream. Another embodiment provides the method wherein thecomposition is a non-homogenous ointment. Another embodiment providesthe method wherein the composition is a non-homogeneous emulsion.Another embodiment provides the method wherein the composition is anon-homogenous dispersion. Another embodiment provides the methodwherein the composition is a non-homogenous cream or a non-homogenouslotion. Another embodiment provides the method wherein the compositionis a non-homogenous lotion.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% ethanol by volume, and atleast one excipient wherein the composition is a non-homogeneoussemisolid and the method is for treatment of acute or sub-acute skindisease or disorder. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid dispersion. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid emulsion. Another embodiment provides the method wherein thecomposition is a non-homogenous cream or a non-homogenous ointment.Another embodiment provides the method wherein the composition is anon-homogenous cream. Another embodiment provides the method wherein thecomposition is a non-homogenous ointment. Another embodiment providesthe method wherein the composition is a non-homogeneous emulsion.Another embodiment provides the method wherein the composition is anon-homogenous dispersion. Another embodiment provides the methodwherein the composition is a non-homogenous cream or a non-homogenouslotion. Another embodiment provides the method wherein the compositionis a non-homogenous lotion.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% ethanol by volume, atleast one moisturizing ingredient and at least one excipient, whereinthe composition is a non-homogeneous semisolid. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid dispersion. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid emulsion. Another embodimentprovides the method wherein the composition is a non-homogenous cream ora non-homogenous ointment. Another embodiment provides the methodwherein the composition is a non-homogenous cream. Another embodimentprovides the method wherein the composition is a non-homogenousointment. Another embodiment provides the method wherein the compositionis a non-homogeneous emulsion. Another embodiment provides the methodwherein the composition is a non-homogenous dispersion. Anotherembodiment provides the method wherein the composition is anon-homogenous cream or a non-homogenous lotion. Another embodimentprovides the method wherein the composition is a non-homogenous lotion.Non-limiting examples of moisturizing ingredients include glycerin,hydrogenated polyisobutene, cetearyl alcohol, macadamia nut oil,dimethicone, tocopheryl acetate, stearoxytrimethylsilane, stearylalcohol, and panthenol.

Another embodiment provides the method wherein the composition comprisesfrom about 2% to about 10% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 2% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 3% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 4% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 5% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 6% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 7% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 8% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 9% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 10% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises from about 6% to about 10% ethanol by volume.Another embodiment provides the method wherein the composition comprisesfrom about 5% to about 10% ethanol by volume.

Another embodiment provides the method wherein the composition comprisesfrom about 10% to about 20% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 11% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 12% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 13% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 14% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 15% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 16% ethanol by volume. Another embodimentprovides the method wherein the composition comprises from about 10% toabout 15% ethanol by volume. Another embodiment provides the methodwherein the composition comprises from about 10% to about 16% ethanol byvolume. Another embodiment provides the method wherein the compositioncomprises from about 10% to about 21% ethanol by volume.

Another embodiment provides the method wherein the composition comprisesfrom about 20% to about 30% ethanol by volume. Another embodimentprovides the method wherein the composition comprises from about 21% toabout 31% ethanol by volume. Another embodiment provides the methodwherein the composition comprises about 25% ethanol by volume. Anotherembodiment provides the method wherein the composition comprises about30% ethanol by volume. Another embodiment provides the method whereinthe composition comprises about 31% ethanol by volume. Anotherembodiment provides the method wherein the composition comprises about32% ethanol by volume. Another embodiment provides the method whereinthe composition comprises from about 25% to about 30% ethanol by volume.Another embodiment provides the method wherein the composition comprisesfrom about 30% to about 35% ethanol by volume. Another embodimentprovides the method wherein the composition comprises from about 30% toabout 40% ethanol by volume. Another embodiment provides the methodwherein the composition comprises from about 40% to about 50% ethanol byvolume. Another embodiment provides the method wherein the compositioncomprises from about 50% to about 55% ethanol by volume.

Another embodiment provides the method wherein the composition isnon-comedogenic.

Another embodiment provides the method wherein the skin disease ordisorder is acne, rosacea, dermatitis, secondarily infected dermatitis,bacterial skin infection, or fungal skin infection. Another embodimentprovides the method wherein the skin disease or disorder is dermatitisor eczema. Another embodiment provides the method wherein the skindisease or disorder is atopic dermatitis.

Another embodiment provides the method wherein topical application ofthe pharmaceutical composition does not irritate the skin. Anotherembodiment provides the method wherein topical application of thepharmaceutical composition does not cause subjective irritation of theskin. Another embodiment provides the method wherein topical applicationof the pharmaceutical composition does not cause a stinging sensation.

Another embodiment provides a method of treating a skin disease ordisorder in an individual by killing or inhibiting the growth ofmicroorganisms. Another embodiment provides the method wherein themicroorganisms are bacteria. Examples of such bacteria include Grampositive and Gram negative aerobic and anaerobic bacteria. Non-limitingexamples of such bacteria include Acinetobacter baumannii, Acinetobacterjohnsonii, Acinetobacter lwoffi, Corynebacterium spp., Enterobacteragglomerans, Enterobacter cloacae, Klebsiella pneumoniae,Propionibacterium acnes, Pseudomonas aeruginosa, Staphylococcus aureus,Staphylococcus epidermidis, Staphylococcus warneri, Streptococcus mitis,and Streptococcus pyogenes. Another embodiment provides the methodwherein the microorganisms are fungi. Non-limiting examples of suchfungi include Candida albicans, Trichophyton mentagrophytes,Trichophyton rubrum, Epidermophyton floccosum, Microsporum audouinii,Microsporum canis, Microsporum fulvum, Microsporum gypseum, andPityrosporum ovale.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% isopropanol by volume,and at least one excipient wherein the composition is a non-homogeneoussemisolid. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid dispersion. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid emulsion. Another embodiment provides the method wherein thecomposition is a non-homogenous cream or a non-homogenous ointment.Another embodiment provides the method wherein the composition is anon-homogenous cream. Another embodiment provides the method wherein thecomposition is a non-homogenous ointment. Another embodiment providesthe method wherein the composition is a non-homogeneous emulsion.Another embodiment provides the method wherein the composition is anon-homogenous dispersion. Another embodiment provides the methodwherein the composition is a non-homogenous cream or a non-homogenouslotion. Another embodiment provides the method wherein the compositionis a non-homogenous lotion. Another embodiment provides the methodwherein the composition comprises from about 2% to about 10% isopropanolby volume. Another embodiment provides the method wherein thecomposition comprises from about 10% to about 20% isopropanol by volume.Another embodiment provides the method wherein the composition comprisesfrom about 20% to about 30% isopropanol by volume. Another embodimentprovides the method wherein the composition comprises from about 30% toabout 40% isopropanol by volume. Another embodiment provides the methodwherein the composition comprises from about 40% to about 50%isopropanol by volume. Another embodiment provides the method whereinthe composition comprises from about 50% to about 59.9% isopropanol byvolume.

Methods of Treatment with a Second Active Ingredient

One embodiment provides a means of applying ethanol to the skin withoutstinging.

One embodiment provides a method of treating a skin disease or disorderin an individual in need thereof comprising topical application to theindividual of a chemical matrix comprising from about 2% to about 30% ofan alcohol by volume, a corticosteroid and at least one excipient,wherein the chemical matrix is an ointment suitable for topicaladministration, the alcohol is primarily dispersed into the chemicalmatrix in the form of microbubbles, and the alcohol is selected fromethanol, isopropanol, or n-propanol.

Another embodiment provides the method wherein the alcohol is ethanol.Another embodiment provides the method wherein the chemical matrixcomprises from about 2% to about 10% ethanol by volume. Anotherembodiment provides the method wherein the chemical matrix comprisesfrom about 10% to about 20% ethanol by volume. Another embodimentprovides the method wherein the chemical matrix comprises from about 20%to about 30% ethanol by volume.

Another embodiment provides the method wherein the ointment is selectedfrom aquaphore, white petrolatum USP, white ointment USP, hydrophilicpetrolatum USP, or hydrophilic ointment USP.

Another embodiment provides the method wherein the corticosteroid isselected from desonide, or mometasone. Another embodiment provides themethod wherein the corticosteroid comprises from about 0.1% (w/w) toabout 0.0001% (w/w) of the chemical matrix. Another embodiment providesthe method wherein the chemical matrix comprises from about 2% to about10% ethanol by volume and the corticosteroid is selected from desonide,or mometasone. Another embodiment provides the method wherein thechemical matrix comprises from about 10% to about 20% ethanol by volumeand the corticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the method wherein the chemical matrix comprisesfrom about 20% to about 30% ethanol by volume and the corticosteroid isselected from desonide, or mometasone.

Another embodiment provides the method wherein the chemical matrixcomprises from about 2% to about 10% ethanol by volume, thecorticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix. Another embodiment provides the method wherein thechemical matrix comprises from about 10% to about 20% ethanol by volume,the corticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix. Another embodiment provides the method wherein thechemical matrix comprises from about 20% to about 30% ethanol by volume,the corticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix.

Another embodiment provides the method wherein the skin disease ordisorder is dermatitis. Another embodiment provides the method whereinthe skin disease or disorder is eczema. Another embodiment provides themethod wherein the skin disease or disorder is atopic dermatitis.

Another embodiment provides the method wherein the alcohol is 1-propanolor 2-propanol. Another embodiment provides the method wherein thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the method wherein the chemical matrix comprisesfrom about 2% to about 10% alcohol by volume. Another embodimentprovides the method wherein the chemical matrix comprises from about 10%to about 20% alcohol by volume. Another embodiment provides the methodwherein the chemical matrix comprises from about 20% to about 30%alcohol by volume. Another embodiment provides the method wherein thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the method wherein the skin disease or disorder isdermatitis. Another embodiment provides the method wherein the skindisease or disorder is eczema. Another embodiment provides the methodwherein the skin disease or disorder is atopic dermatitis.

One embodiment provides a method of treating a skin disease or disorderin an individual comprising topical application of a pharmaceuticalcomposition suitable for topical administration comprising from about 2%to no more than 59.9% of an alcohol by volume, a second activeingredient, and at least one excipient wherein the composition is anon-homogeneous semisolid and the alcohol is selected from ethanol,isopropanol, or n-propanol. One embodiment provides a method of treatinga skin disease or disorder in an individual comprising topicalapplication of a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% ethanol byvolume, a second active ingredient, and at least one excipient whereinthe composition is a non-homogeneous semisolid. Another embodimentprovides the method wherein the composition is a non-homogenoussemisolid dispersion. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid emulsion. Another embodimentprovides the method wherein the composition is a non-homogenous cream ora non-homogenous ointment. Another embodiment provides the methodwherein the composition is a non-homogenous cream. Another embodimentprovides the method wherein the composition is a non-homogenousointment.

One embodiment provides a method of treating a skin disease or disorderin an individual comprising topical application of a pharmaceuticalcomposition suitable for topical administration comprising from about 2%to no more than 59.9% of an alcohol by volume, a second activeingredient, and at least one excipient wherein the composition is anon-homogeneous emulsion and the alcohol is selected from ethanol,isopropanol, or n-propanol. Another embodiment provides a method oftreating a skin disease or disorder in an individual comprising topicalapplication of a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% ethanol byvolume, a second active ingredient, and at least one excipient whereinthe composition is a non-homogeneous emulsion. Another embodimentprovides the method wherein the composition is a non-homogenousdispersion. Another embodiment provides the method wherein thecomposition is a non-homogenous cream or a non-homogenous lotion.Another embodiment provides the method wherein the composition is anon-homogenous cream. Another embodiment provides the method wherein thecomposition is a non-homogenous lotion.

Another embodiment provides the method wherein the composition comprisesfrom about 2% to about 10% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 2% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 3% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 4% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 5% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 6% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 7% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 8% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 9% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 10% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises from about 6% to about 10% ethanol by volume.Another embodiment provides the method wherein the composition comprisesfrom about 5% to about 10% ethanol by volume.

Another embodiment provides the method wherein the composition comprisesfrom about 10% to about 20% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 11% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 12% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 13% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 14% ethanol by volume. Another embodimentprovides the method wherein the composition comprises about 15% ethanolby volume. Another embodiment provides the method wherein thecomposition comprises about 16% ethanol by volume. Another embodimentprovides the method wherein the composition comprises from about 10% toabout 15% ethanol by volume. Another embodiment provides the methodwherein the composition comprises from about 10% to about 16% ethanol byvolume. Another embodiment provides the method wherein the compositioncomprises from about 10% to about 21% ethanol by volume.

Another embodiment provides the method wherein the composition comprisesfrom about 20% to about 30% ethanol by volume. Another embodimentprovides the method wherein the composition comprises from about 21% toabout 31% ethanol by volume. Another embodiment provides the methodwherein the composition comprises about 25% ethanol by volume. Anotherembodiment provides the method wherein the composition comprises about30% ethanol by volume. Another embodiment provides the method whereinthe composition comprises about 31% ethanol by volume. Anotherembodiment provides the method wherein the composition comprises about32% ethanol by volume. Another embodiment provides the method whereinthe composition comprises from about 25% to about 30% ethanol by volume.Another embodiment provides the method wherein the composition comprisesfrom about 30% to about 35% ethanol by volume. Another embodimentprovides the method wherein the composition comprises from about 30% toabout 40% ethanol by volume. Another embodiment provides the methodwherein the composition comprises from about 40% to about 50% ethanol byvolume. Another embodiment provides the method wherein the compositioncomprises from about 50% to about 55% ethanol by volume.

Another embodiment provides the method wherein the composition isnon-comedogenic.

Another embodiment provides the method wherein the skin disease ordisorder is acne, rosacea, dermatitis, secondarily infected dermatitis,bacterial skin infection, or fungal skin infection. Another embodimentprovides the method wherein the skin disease or disorder is dermatitisor eczema. Another embodiment provides the method wherein the skindisease or disorder is atopic dermatitis.

Another embodiment provides the method wherein the second activeingredient is a corticosteroid selected from 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone diacetonide, and triamcinolone hexacetonide; and apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof.

Another embodiment provides the method wherein the second activeingredient is a corticosteroid selected from hydrocortisone, desonide,mometasone, betamethasone, fluticasone, fluocinolone, triamcinolone,triamcinolone acetonide, triamcinolone diacetonide, or clobetasol; and apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof. Another embodiment provides the pharmaceuticalcomposition wherein the second active ingredient is a corticosteroidselected from hydrocortisone, desonide, mometasone, triamcinolone,triamcinolone acetonide, triamcinolone diacetonide, fluocinolone orfluticasone; and a pharmaceutically acceptable salt thereof, orphosphate prodrug thereof, or ester prodrug thereof. Another embodimentprovides the pharmaceutical composition wherein the second activeingredient is hydrocortisone or a pharmaceutically acceptable saltthereof, or phosphate prodrug thereof, or ester prodrug thereof. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is desonide, or a pharmaceutically acceptable saltthereof, or phosphate prodrug thereof, or ester prodrug thereof. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is mometasone. Another embodiment provides thepharmaceutical composition wherein the second active ingredient isfluticasone, or a pharmaceutically acceptable salt thereof, or phosphateprodrug thereof, or ester prodrug thereof. Another embodiment providesthe pharmaceutical composition wherein the second active ingredient isfluocinolone. Another embodiment provides the pharmaceutical compositionwherein the second active ingredient is triamcinolone.

Another embodiment provides the method wherein the second activeingredient is a corticosteroid. Another embodiment provides the methodwherein the second active ingredient is a corticosteroid selected from21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide, or a phosphate or ester prodrug thereof.

Another embodiment provides the method wherein the second activeingredient is a corticosteroid selected from hydrocortisone, desonide,mometasone, betamethasone, fluticasone, triamcinolone, fluocinolone orclobetasol. Another embodiment provides the method wherein the secondactive ingredient is a corticosteroid selected from hydrocortisone,desonide, mometasone, fluocinolone, triamcinolone or fluticasone.Another embodiment provides the method wherein the second activeingredient is hydrocortisone. Another embodiment provides the methodwherein the second active ingredient is desonide. Another embodimentprovides the method wherein the second active ingredient is mometasone.Another embodiment provides the method wherein the second activeingredient is fluticasone. Another embodiment provides the methodwherein the second active ingredient is fluocinolone. Another embodimentprovides the method wherein the second active ingredient istriamcinolone.

Another embodiment provides the method wherein topical application ofthe pharmaceutical composition does not irritate the skin. Anotherembodiment provides the method wherein topical application of thepharmaceutical composition does not cause subjective irritation of theskin. Another embodiment provides the method wherein topical applicationof the pharmaceutical composition does not cause a stinging sensation.

Another embodiment provides a method of treating a skin disease ordisorder in an individual comprising topical application of apharmaceutical composition suitable for topical administrationcomprising from about 2% to no more than 59.9% isopropanol by volume, asecond active ingredient, and at least one excipient wherein thecomposition is a non-homogeneous semisolid. Another embodiment providesthe method wherein the composition is a non-homogenous semisoliddispersion. Another embodiment provides the method wherein thecomposition is a non-homogenous semisolid emulsion. Another embodimentprovides the method wherein the composition is a non-homogenous cream ora non-homogenous ointment. Another embodiment provides the methodwherein the composition is a non-homogenous cream. Another embodimentprovides the method wherein the composition is a non-homogenousointment. Another embodiment provides the method wherein the compositionis a non-homogeneous emulsion. Another embodiment provides the methodwherein the composition is a non-homogenous dispersion. Anotherembodiment provides the method wherein the composition is anon-homogenous cream or a non-homogenous lotion. Another embodimentprovides the method wherein the composition is a non-homogenous lotion.Another embodiment provides the method wherein the composition comprisesfrom about 2% to about 10% isopropanol by volume. Another embodimentprovides the method wherein the composition comprises from about 10% toabout 20% isopropanol by volume. Another embodiment provides the methodwherein the composition comprises from about 20% to about 30%isopropanol by volume. Another embodiment provides the method whereinthe composition comprises from about 30% to about 40% isopropanol byvolume. Another embodiment provides the method wherein the compositioncomprises from about 40% to about 50% isopropanol by volume. Anotherembodiment provides the method wherein the composition comprises fromabout 50% to about 59.9% isopropanol by volume.

In some of the methods of treatment disclosed herein, the ratio ofethanol to the second active ingredient in the non-homogeneouscomposition is fixed during the course of treatment. In some of themethods of treatment disclosed herein, the ratio of ethanol to thesecond active ingredient in the non-homogeneous composition varies asdirected by a physician during the course of treatment. Topicalapplication of the non-homogeneous composition can occur one to fourtimes a day or as directed by a physician. The duration of treatment canvary from one to four weeks or as directed by a physician. In some ofthe methods of treatment disclosed herein, a non-homogeneous compositioncomprising ethanol and a second active ingredient is topically appliedduring the initial course of treatment prior to replacement with anothernon-homogeneous composition comprising ethanol as maintenance therapy.The course of treatment can optionally include pre-treatment of the areawith soap and water and/or occlusion of the treatment area subsequent toapplication of the non-homogeneous composition described herein.

One embodiment provides the method of treating a skin disease ordisorder in an individual comprising topical application of anon-homogeneous pharmaceutical composition suitable for topicaladministration from one to four times a day comprising a fixed ratio ofthe ethanol and the second active ingredient during the duration oftreatment. Another embodiment provides the method wherein the durationof treatment is two weeks. Another embodiment provides the methodwherein the duration of treatment is three weeks. Another embodimentprovides the method wherein the duration of treatment is four weeks.Another embodiment provides the method wherein the topicaladministration is once a day. Another embodiment provides the methodwherein the topical administration is twice a day. Another embodimentprovides the method wherein the topical administration is three times aday. Another embodiment provides the method wherein the topicaladministration is four times a day. Another embodiment provides themethod of treating a skin disease or disorder in an individualcomprising topical application of a pharmaceutical composition suitablefor topical administration as directed by a physician comprising a fixedratio of the ethanol and the second active ingredient during theduration of treatment.

Another embodiment provides the method wherein the non-homogeneouscomposition comprising a fixed ratio of the ethanol and the secondactive ingredient contains 5% ethanol by volume. Another embodimentprovides the method wherein the non-homogeneous composition comprising afixed ratio of the ethanol and the second active ingredient contains 6%ethanol by volume. Another embodiment provides the method wherein thenon-homogeneous composition comprising a fixed ratio of the ethanol andthe second active ingredient contains 7% ethanol by volume. Anotherembodiment provides the method wherein the non-homogeneous compositioncomprising a fixed ratio of the ethanol and the second active ingredientcontains 10% ethanol by volume. Another embodiment provides the methodwherein the non-homogeneous composition comprising a fixed ratio of theethanol and the second active ingredient contains 12% ethanol by volume.Another embodiment provides the method wherein the non-homogeneouscomposition comprising a fixed ratio of the ethanol and the secondactive ingredient contains 16% ethanol by volume. Another embodimentprovides the method wherein the non-homogeneous composition comprising afixed ratio of the ethanol and the second active ingredient contains 21%ethanol by volume. Another embodiment provides the method wherein thenon-homogeneous composition comprising a fixed ratio of the ethanol andthe second active ingredient contains 31% ethanol by volume.

Another embodiment provides the method of treating a skin disease ordisorder in an individual comprising topical application of anon-homogeneous pharmaceutical composition suitable for topicaladministration from one to four times a day as part of a progressiveratio therapy in which the percentage of ethanol is increased every 2-3days during the duration of treatment. Another embodiment provides themethod wherein the duration of treatment is two weeks. Anotherembodiment provides the method wherein the duration of treatment isthree weeks. Another embodiment provides the method wherein the durationof treatment is four weeks. Another embodiment provides the methodwherein the topical administration is once a day. Another embodimentprovides the method wherein the topical administration is twice a day.Another embodiment provides the method wherein the topicaladministration is three times a day. Another embodiment provides themethod wherein the topical administration is four times a day. Anotherembodiment provides the method of treating a skin disease or disorder inan individual comprising topical application of a pharmaceuticalcomposition suitable for topical administration as directed by aphysician during the duration of treatment.

Another embodiment provides the method wherein the percentage of ethanolis increased every 2 days during the duration of treatment. Anotherembodiment provides the method wherein the percentage of ethanol isincreased every 3 days during the duration of treatment. Anotherembodiment provides the method wherein the percentage of ethanol isincreased when there is visible improvement of the skin condition duringthe duration of treatment. Another embodiment provides the method oftreating a skin disease or disorder in an individual comprising topicalapplication of a non-homogeneous pharmaceutical composition suitable fortopical administration from one to four times a day as part of aprogressive ratio therapy in which the percentage of ethanol wasincreased as directed by a physician during the duration of treatment.

Another embodiment provides the method wherein the initial percentage ofethanol is 5% and the final percentage of ethanol is 31% during theduration of treatment. Another embodiment provides the method whereinthe initial percentage of ethanol is 7% and the final percentage ofethanol is 31% during the duration of treatment. Another embodimentprovides the method wherein the initial percentage of ethanol is 10% andthe final percentage of ethanol is 31% during the duration of treatment.Another embodiment provides the method wherein the initial percentage ofethanol is about 5% to about 10% and the final percentage of ethanol is31% during the duration of treatment.

Compositions for the Treatment of Skin Diseases and Disorders

The compositions described herein are non-homogenous. In particular, ithas been found that when the alcohol, selected from ethanol, propanol,or iso-propanol, is distributed in a non-homogenous fashion throughoutthe bulk of the composition or matrix into bubble-like regions oflocally high concentration, referred to herein as microbubbles, whereinthe approximate effective concentration of the alcohol inside themicrobubbles is about 60% to about 80%, a beneficial effect is observedupon topical application to damaged skin but without a stingingsensation. In the compositions described herein, a key aspect is therole of the alcohol. The alcohol, selected from ethanol, propanol, oriso-propanol, functions as an active ingredient of the compositionhaving an antiseptic activity and not merely as a solvent or excipient.

In some embodiments, the microbubbles are dispersed into a chemicalmatrix which is an ointment. In other embodiments, the microbubbles aredispersed into a chemical matrix which is a semi-solid. In otherembodiments, the microbubbles are dispersed into a chemical matrix whichis a cream.

One embodiment provides a chemical matrix comprising from about 2% toabout 30% of an alcohol by volume, a corticosteroid and at least oneexcipient, wherein the chemical matrix is an ointment suitable fortopical administration, the alcohol is primarily dispersed into thechemical matrix in the form of microbubbles, and the alcohol is selectedfrom ethanol, isopropanol, or n-propanol.

Another embodiment provides the chemical matrix wherein the alcohol isethanol. Another embodiment provides the chemical matrix wherein thechemical matrix comprises from about 2% to about 10% ethanol by volume.Another embodiment provides the chemical matrix wherein the chemicalmatrix comprises from about 10% to about 20% ethanol by volume. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 20% to about 30% ethanol by volume.

Another embodiment provides the chemical matrix wherein the ointment isselected from aquaphore, white petrolatum USP, white ointment USP,hydrophilic petrolatum USP, or hydrophilic ointment USP.

Another embodiment provides the chemical matrix wherein thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the corticosteroidcomprises from about 0.1% (w/w) to about 0.0001% (w/w) of the chemicalmatrix. Another embodiment provides the chemical matrix wherein thecorticosteroid comprises from about 0.1% (w/w) to about 0.001% (w/w) ofthe chemical matrix. Another embodiment provides the chemical matrixwherein the corticosteroid comprises from about 0.1% (w/w) to about0.01% (w/w) of the chemical matrix. Another embodiment provides thechemical matrix wherein the corticosteroid comprises from about 0.1%(w/w) to about 0.005% (w/w) of the chemical matrix. Another embodimentprovides the chemical matrix wherein the corticosteroid comprises fromabout 0.1% (w/w) to about 0.05% (w/w) of the chemical matrix. Anotherembodiment provides the chemical matrix wherein the corticosteroidcomprises from about 0.05% (w/w) to about 0.005% (w/w) of the chemicalmatrix. Another embodiment provides the chemical matrix wherein thechemical matrix comprises from about 2% to about 10% ethanol by volumeand the corticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 10% to about 20% ethanol by volume and thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 20% to about 30% ethanol by volume and thecorticosteroid is selected from desonide, or mometasone.

Another embodiment provides the chemical matrix wherein the chemicalmatrix comprises from about 2% to about 10% ethanol by volume, thecorticosteroid is selected from desonide, or mometasone, and thecorticosteroid comprises from about 0.1% (w/w) to about 0.0001% (w/w) ofthe chemical matrix. Another embodiment provides the chemical matrixwherein the chemical matrix comprises from about 10% to about 20%ethanol by volume, the corticosteroid is selected from desonide, ormometasone, and the corticosteroid comprises from about 0.1% (w/w) toabout 0.0001% (w/w) of the chemical matrix. Another embodiment providesthe chemical matrix wherein the chemical matrix comprises from about 20%to about 30% ethanol by volume, the corticosteroid is selected fromdesonide, or mometasone, and the corticosteroid comprises from about0.1% (w/w) to about 0.0001% (w/w) of the chemical matrix.

Another embodiment provides the chemical matrix wherein the alcohol is1-propanol. Another embodiment provides the chemical matrix wherein thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 2% to about 10% 1-propanol by volume. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 10% to about 20% 1-propanol by volume. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 20% to about 30% 1-propanol by volume. Anotherembodiment provides the chemical matrix wherein the corticosteroid isselected from desonide, or mometasone.

Another embodiment provides the chemical matrix wherein the alcohol is2-propanol. Another embodiment provides the chemical matrix wherein thecorticosteroid is selected from desonide, or mometasone. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 2% to about 10% 2-propanol by volume. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 10% to about 20% 2-propanol by volume. Anotherembodiment provides the chemical matrix wherein the chemical matrixcomprises from about 20% to about 30% 2-propanol by volume. Anotherembodiment provides the chemical matrix wherein the corticosteroid isselected from desonide, or mometasone. Another embodiment provides thechemical matrix wherein the corticosteroid is selected from desonide, ormometasone. Another embodiment provides the chemical matrix wherein thecorticosteroid is selected from desonide, or mometasone.

One embodiment provides a pharmaceutical composition suitable fortopical administration comprising from about 2% to no more than 59.9% ofan alcohol by volume, a second active ingredient and at least oneexcipient wherein said composition is a non-homogeneous semisolid andthe alcohol is selected from ethanol, isopropanol, or n-propanol. Oneembodiment provides a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% ethanol byvolume, a second active ingredient and at least one excipient whereinsaid composition is a non-homogeneous semisolid. Another embodimentprovides the pharmaceutical composition as a semisolid dispersion.Another embodiment provides the pharmaceutical composition as asemisolid emulsion. Another embodiment provides the pharmaceuticalcomposition as a non-homogenous cream or a non-homogenous ointment.Another embodiment provides the pharmaceutical composition as anon-homogenous ointment. Another embodiment provides the pharmaceuticalcomposition as a non-homogenous cream.

One embodiment provides a pharmaceutical composition suitable fortopical administration comprising from about 2% to no more than 59.9% ofan alcohol by volume, a second active ingredient and at least oneexcipient wherein said composition is a non-homogeneous emulsion and thealcohol is selected from ethanol, isopropanol, or n-propanol. Oneembodiment provides a pharmaceutical composition suitable for topicaladministration comprising from about 2% to no more than 59.9% ethanol byvolume, a second active ingredient and at least one excipient whereinsaid composition is a non-homogenous emulsion. Another embodimentprovides the pharmaceutical composition as a dispersion. Anotherembodiment provides the pharmaceutical composition as a non-homogenouscream or a non-homogenous lotion. Another embodiment provides thepharmaceutical composition as a non-homogenous lotion. Anotherembodiment provides the pharmaceutical composition as a non-homogenouscream.

Another embodiment provides the pharmaceutical composition wherein thesecond active ingredient is selected from salicylic acid, glycolic acid,benzoyl peroxide, sulfur, resorcinol, tretinoin, adapalene, tazarotene,clindamycin or erythromycin. Another embodiment provides thepharmaceutical composition wherein the second active ingredient isselected from salicylic acid, glycolic acid, benzoyl peroxide, sulfur,resorcinol, tretinoin, adapalene, tazarotene, clindamycin, erythromycin,metronidazole, or azelaic acid. Another embodiment provides thepharmaceutical composition wherein the second active ingredient isselected from salicylic acid, terbenafine, econazole, miconazole,clotrimazole, butenafine, or tolnaftate. Another embodiment provides thepharmaceutical composition wherein the second active is not menthol.

Another embodiment provides the pharmaceutical composition wherein thesecond active ingredient is a corticosteroid. Another embodimentprovides the pharmaceutical composition wherein the second activeingredient is selected from a corticosteroid, tar derivatives, salicylicacid, calcipotriene, or anthralin.

Another embodiment provides the pharmaceutical composition wherein thesecond active ingredient is a corticosteroid selected from21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonediacetonide, and triamcinolone hexacetonide; and a pharmaceuticallyacceptable salt thereof, or phosphate prodrug thereof, or ester prodrugthereof.

Another embodiment provides the pharmaceutical composition wherein thesecond active ingredient is a corticosteroid selected fromhydrocortisone, desonide, mometasone, betamethasone, fluticasone,fluocinolone, triamcinolone, triamcinolone acetonide, triamcinolonediacetonide, or clobetasol; and a pharmaceutically acceptable saltthereof, or phosphate prodrug thereof, or ester prodrug thereof. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is a corticosteroid selected from hydrocortisone,desonide, mometasone, triamcinolone, triamcinolone acetonide,triamcinolone diacetonide, fluocinolone or fluticasone; and apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof. Another embodiment provides the pharmaceuticalcomposition wherein the second active ingredient is hydrocortisone or apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof. Another embodiment provides the pharmaceuticalcomposition wherein the second active ingredient is desonide, or apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof. Another embodiment provides the pharmaceuticalcomposition wherein the second active ingredient is mometasone. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is fluticasone, or a pharmaceutically acceptable saltthereof, or phosphate prodrug thereof, or ester prodrug thereof. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is fluocinolone. Another embodiment provides thepharmaceutical composition wherein the second active ingredient istriamcinolone.

The numerous corticosteroids have been classified by several protocols.Classification by chemical structure is known as the Coopmanclassification and is indicated below.

Group A—Hydrocortisone Type

-   -   hydrocortisone, hydrocortisone acetate, cortisone acetate,        tixocortol pivalate, prednisolone, methylprednisolone, and        prednisone (short- to medium-acting glucocorticoids)

Group B—Acetonides (and related substances)

-   -   triamcinolone acetonide, triamcinolone alcohol, mometasone,        amcinonide, budesonide, desonide, fluocinonide, fluocinolone        acetonide, and halcinonide

Group C—Betamethasone Type

-   -   betamethasone, betamethasone sodium phosphate, dexamethasone,        dexamethasone sodium phosphate, and fluocortolone

Group D—Esters

Group D1—Halogenated (Less Labile)

-   -   hydrocortisone-17-valerate, aclometasone dipropionate,        betamethasone valerate, betamethasone dipropionate,        prednicarbate, clobetasone-17-butyrate,        clobetasol-17-propionate, fluocortolone caproate, fluocortolone        pivalate, and fluprednidene acetate

Group D2—Labile Prodrug Esters

-   -   hydrocortisone-17-butyrate, 17-aceponate, 17-buteprate, and        prednicarbate

The Coopman classification is particularly useful in cases where acertain corticosteroid serves an allergen. In this situation allergicreactions to one member of a class typically indicate an intolerance ofall members of the class.

An alternative classification protocol involves grouping by strength inan standard vasoconstriction assay (Ference and Last, Am Fam Physician.2009, Jan. 15; 79(2):135-140). In this protocol, seven potency groupshave been established ranging from high potency to low potency.

Ultra high (I) Augmented betamethasone dipropionate 0.05%

-   -   Clobetasol propionate 0.05%    -   Diflorasone diacetate 0.05%    -   Fluocinonide 0.1%    -   Flurandrenolide 0.05%        High (II) Amcinonide 0.1%    -   Augmented betamethasone dipropionate 0.05%    -   Betamethasone dipropionate 0.05%    -   Desoximetasone 0.25%    -   Diflorasone diacetate 0.05%    -   Fluocinonide 0.05%    -   Halcinonide 0.1%    -   Halobetasol propionate 0.05%        Medium to high (III) Amcinonide 0.1%    -   Betamethasone dipropionate 0.05%    -   Fluticasone propionate 0.005%    -   Triamcinolone acetonide 0.5%    -   Halobetasol propionate 0.05%        Medium (IV and V) Betamethasone valerate 0.1%    -   Desoximetasone 0.05%    -   Fluocinolone acetonide 0.025%    -   Fluticasone propionate 0.05%    -   Hydrocortisone butyrate 0.1%    -   Hydrocortisone probutate 0.1%    -   Hydrocortisone valerate 0.2%    -   Mometasone furoate 0.1%    -   Triamcinolone acetonide 0.025%    -   Triamcinolone acetonide 0.1%        Low (VI) Alclometasone dipropionate 0.05%    -   Desonide 0.05%    -   Fluocinolone 0.01%    -   Hydrocortisone butyrate 0.1%        Least potent (VII) Hydrocortisone 1%, 2.5%

Ultra-high-potency topical steroids should not be used continuously forlonger than three weeks. Low- to high-potency topical steroids shouldnot be used continuously for longer than three months to avoid sideeffects. Prolonged use of topical corticosteroids may cause sideeffects. To reduce the risk, the least potent steroid should be used forthe shortest time, while still maintaining effectiveness.

In addition to allowing for the use of an antiseptic alcohol, such asethanol, 1-propanol, or 2-propanol, in a manner which avoids stingingwhen applied to cracked or damaged skin, the compositions and methodsdescribed herein allow for the use of corticosteroids at lowerconcentrations than previously employed while maintaining efficacy. Thebenefits derived from this treatment regimen at lower doses ofcorticosteroid are several. First, a lower dose or exposure level ofcorticosteroid will result in fewer side effects from corticosteroiduse. Second, if lower doses or exposure levels are possible, theattending physician may elect to use a more potent corticosteroid fordifficult to treat cases. Also, the use of the more potentcorticosteroid may allow for faster resolution of dermatologicalcondition and an overall shortening of the period of time during whichthe patient is undergoing therapy. Thus, one advantage of thecompositions and methods described herein is that the compositionsdescribed herein provide equal or greater efficacy than currentlyaccepted treatments but at a lower exposure level of corticosteroid tothe patient.

In some embodiments, the amount of corticosteroid present in theformulation is equivalent to the FDA approved wt %. In otherembodiments, the amount of corticosteroid present in the formulation isabout 100% of the FDA approved wt %. In other embodiments, the amount ofcorticosteroid present in the formulation is about 90% of the FDAapproved wt %. In other embodiments, the amount of corticosteroidpresent in the formulation is about 80% of the FDA approved wt %. Inother embodiments, the amount of corticosteroid present in theformulation is about 70% of the FDA approved wt %. In other embodiments,the amount of corticosteroid present in the formulation is about 60% ofthe FDA approved wt %. In other embodiments, the amount ofcorticosteroid present in the formulation is about 50% of the FDAapproved wt %. In other embodiments, the amount of corticosteroidpresent in the formulation is about 40% of the FDA approved wt %. Inother embodiments, the amount of corticosteroid present in theformulation is about 30% of the FDA approved wt %. In other embodiments,the amount of corticosteroid present in the formulation is about 20% ofthe FDA approved wt %. In other embodiments, the amount ofcorticosteroid present in the formulation is about 10% of the FDAapproved wt %. In other embodiments, the amount of corticosteroidpresent in the formulation is about 5% of the FDA approved wt %. Inother embodiments, the amount of corticosteroid present in theformulation is about 4% of the FDA approved wt %. In other embodiments,the amount of corticosteroid present in the formulation is about 3% ofthe FDA approved wt %. In other embodiments, the amount ofcorticosteroid present in the formulation is about 2% of the FDAapproved wt %. In other embodiments, the amount of corticosteroidpresent in the formulation is about 1% of the FDA approved wt %.

A feature of the non-homogenous chemical matrices and compositionsdescribed herein is the compartmentalized or segregated nature of thematrices and compositions. As described herein the alcohol, selectedfrom ethanol, 1-propanol or 2-propanol, is located primarily within themicrobubbles and the microbubbles are dispersed into the chemicalmatrix. The corticosteroid or other second active ingredient, however,is dispersed primarily in the chemical matrix and is not foundsubstantially within the microbubbles. In some embodiments, at least 95%of the alcohol is located within the microbubble. In some embodiments,at least 90% of the alcohol is located within the microbubble. In someembodiments, at least 85% of the alcohol is located within themicrobubble. In some embodiments, at least 80% of the alcohol is locatedwithin the microbubble. In some embodiments, at least 75% of the alcoholis located within the microbubble. In some embodiments, at least 70% ofthe alcohol is located within the microbubble. In some embodiments, atleast 65% of the alcohol is located within the microbubble. In someembodiments, at least 60% of the alcohol is located within themicrobubble. In some embodiments, at least 55% of the alcohol is locatedwithin the microbubble. In some embodiments, at least 50% of the alcoholis located within the microbubble.rd

Another embodiment provides the pharmaceutical composition wherein thecomposition comprises about 2% ethanol by volume. Another embodimentprovides the pharmaceutical composition wherein the compositioncomprises about 3% ethanol by volume. Another embodiment provides thepharmaceutical composition wherein the composition comprises about 4%ethanol by volume. Another embodiment provides the pharmaceuticalcomposition wherein the composition comprises about 5% ethanol byvolume. Another embodiment provides the pharmaceutical compositionwherein the composition comprises about 6% ethanol by volume. Anotherembodiment provides the pharmaceutical composition wherein thecomposition comprises about 7% ethanol by volume. Another embodimentprovides the pharmaceutical composition wherein the compositioncomprises about 8% ethanol by volume. Another embodiment provides thepharmaceutical composition wherein the composition comprises about 9%ethanol by volume. Another embodiment provides the pharmaceuticalcomposition wherein the composition comprises about 10% ethanol byvolume. Another embodiment provides the pharmaceutical compositionwherein the composition comprises from about 6% to about 10% ethanol byvolume. Another embodiment provides the pharmaceutical compositionwherein the composition comprises from about 2% to about 10% ethanol byvolume. Another embodiment provides the pharmaceutical compositionwherein the composition comprises from about 5% to about 10% ethanol byvolume.

Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 10% to about 20% ethanol by volume.Another embodiment provides the pharmaceutical composition wherein thecomposition comprises about 11% ethanol by volume. Another embodimentprovides the pharmaceutical composition wherein the compositioncomprises about 12% ethanol by volume. Another embodiment provides thepharmaceutical composition wherein the composition comprises about 13%ethanol by volume. Another embodiment provides the pharmaceuticalcomposition wherein the composition comprises about 14% ethanol byvolume. Another embodiment provides the pharmaceutical compositionwherein the composition comprises about 15% ethanol by volume. Anotherembodiment provides the pharmaceutical composition wherein thecomposition comprises about 16% ethanol by volume. Another embodimentprovides the pharmaceutical composition wherein the compositioncomprises from about 10% to about 15% ethanol by volume. Anotherembodiment provides the pharmaceutical composition wherein thecomposition comprises from about 10% to about 16% ethanol by volume.Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 10% to about 21% ethanol by volume.

Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 20% to about 30% ethanol by volume.Another embodiment provides the method wherein the composition comprisesfrom about 21% to about 31% ethanol by volume. Another embodimentprovides the pharmaceutical composition wherein the compositioncomprises about 25% ethanol by volume. Another embodiment provides thepharmaceutical composition wherein the composition comprises about 30%ethanol by volume. Another embodiment provides the pharmaceuticalcomposition wherein the composition comprises about 31% ethanol byvolume. Another embodiment provides the pharmaceutical compositionwherein the composition comprises about 32% ethanol by volume. Anotherembodiment provides the pharmaceutical composition wherein thecomposition comprises from about 25% to about 30% ethanol by volume.Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 30% to about 35% ethanol by volume.Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 30% to about 40% ethanol by volume.Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 40% to about 50% ethanol by volume.Another embodiment provides the pharmaceutical composition wherein thecomposition comprises from about 50% to about 55% ethanol by volume.

All non-homogeneous pharmaceutical compositions comprising ethanoldisclosed herein do not contain greater than 59.9% ethanol.

Another embodiment provides the pharmaceutical composition wherein thecomposition is non-comedogenic.

Another embodiment provides the pharmaceutical composition whereintopical application of the pharmaceutical composition does not irritatethe skin. Another embodiment provides the pharmaceutical compositionwherein topical application of the pharmaceutical composition does notcause subjective irritation of the skin. Another embodiment provides thepharmaceutical composition wherein topical application of thepharmaceutical composition does not cause a stinging sensation.

The compositions described herein contain alcohols which provide anantiseptic effect when applied to the skin in high concentrations. Byvirtue of the non-homogenous nature of the compositions describedherein, topical application of these compositions does not produce astinging sensation when applied to the skin. These alcohols are selectedfrom ethanol, isopropanol (2-propanol), or n-propanol (1-propanol),(Kampf et al, Clin. Microbiol. Rev. (2004), 17(4), 863-93; FederalRegister Vol. 47, No. 99, Friday, May 21, 1982, pages 22324-22333).Based on the disclosure provided herein a skilled practitioner canprepare and use the compositions described herein comprising ethanol,isopropanol or n-propanol. For the compositions containing isopropanolthe approximate effective concentration in the bubble-like regions oflocally high concentration is about 60% to about 80%. For thecompositions containing n-propanol the approximate effectiveconcentration in the bubble-like regions of locally high concentrationis about 60% to about 80%.

One embodiment provides a pharmaceutical composition suitable fortopical administration comprising from about 2% to no more than 59.9%isopropanol by volume, a second active ingredient and at least oneexcipient wherein said composition is a non-homogeneous semisolid.Another embodiment provides the pharmaceutical composition as asemisolid dispersion. Another embodiment provides the pharmaceuticalcomposition as a semisolid emulsion. Another embodiment provides thepharmaceutical composition as a non-homogenous cream or a non-homogenousointment. Another embodiment provides the pharmaceutical composition asa non-homogenous ointment. Another embodiment provides thepharmaceutical composition as a non-homogenous cream.

One embodiment provides a pharmaceutical composition suitable fortopical administration comprising from about 2% to no more than 59.9%isopropanol by volume, a second active ingredient and at least oneexcipient wherein said composition is a non-homogenous emulsion. Anotherembodiment provides the pharmaceutical composition as a dispersion.Another embodiment provides the pharmaceutical composition as anon-homogenous cream or a non-homogenous lotion. Another embodimentprovides the pharmaceutical composition as a non-homogenous lotion.Another embodiment provides the pharmaceutical composition as anon-homogenous cream.

Another embodiment provides the composition wherein the compositioncomprises from about 2% to about 10% isopropanol by volume. Anotherembodiment provides the composition wherein the composition comprisesfrom about 10% to about 20% isopropanol by volume. Another embodimentprovides the composition wherein the composition comprises from about20% to about 30% isopropanol by volume. Another embodiment provides thecomposition wherein the composition comprises from about 30% to about40% isopropanol by volume. Another embodiment provides the compositionwherein the composition comprises from about 40% to about 50%isopropanol by volume. Another embodiment provides the compositionwherein the composition comprises from about 50% to about 59.9%isopropanol by volume. All non-homogeneous pharmaceutical compositionscomprising isopropanol disclosed herein do not contain greater than59.9% isopropanol.

One embodiment provides a pharmaceutical composition suitable fortopical administration comprising from about 2% to no more than 59.9%n-propanol by volume, a second active ingredient and at least oneexcipient wherein said composition is a non-homogeneous semisolid.Another embodiment provides the pharmaceutical composition as asemisolid dispersion. Another embodiment provides the pharmaceuticalcomposition as a semisolid emulsion. Another embodiment provides thepharmaceutical composition as a non-homogenous cream or a non-homogenousointment. Another embodiment provides the pharmaceutical composition asa non-homogenous ointment. Another embodiment provides thepharmaceutical composition as a non-homogenous cream.

One embodiment provides a pharmaceutical composition suitable fortopical administration comprising from about 2% to no more than 59.9%n-propanol by volume, a second active ingredient and at least oneexcipient wherein said composition is a non-homogenous emulsion. Anotherembodiment provides the pharmaceutical composition as a dispersion.Another embodiment provides the pharmaceutical composition as anon-homogenous cream or a non-homogenous lotion. Another embodimentprovides the pharmaceutical composition as a non-homogenous lotion.Another embodiment provides the pharmaceutical composition as anon-homogenous cream.

Another embodiment provides the composition wherein the compositioncomprises from about 2% to about 10% n-propanol by volume. Anotherembodiment provides the composition wherein the composition comprisesfrom about 10% to about 20% n-propanol by volume. Another embodimentprovides the composition wherein the composition comprises from about20% to about 30% n-propanol by volume. Another embodiment provides thecomposition wherein the composition comprises from about 30% to about40% n-propanol by volume. Another embodiment provides the compositionwherein the composition comprises from about 40% to about 50% n-propanolby volume. Another embodiment provides the composition wherein thecomposition comprises from about 50% to about 59.9% n-propanol byvolume. All non-homogeneous pharmaceutical compositions comprisingn-propanol disclosed herein do not contain greater than 59.9%n-propanol.

In some embodiments, a pharmaceutical composition suitable for topicaladministrations described herein exhibits a viscosity of between about10,000 and about 1,000,000 centipoise. In some embodiments, apharmaceutical composition suitable for topical administrationsdescribed herein exhibits a viscosity of between about 50,000 and about1,000,000 centipoise. In some embodiments, a pharmaceutical compositionsuitable for topical administrations described herein exhibits aviscosity of between about 150,000 and about 1,000,000 centipoise. Insome embodiments, a pharmaceutical composition suitable for topicaladministrations described herein exhibits a viscosity of between about50,000 and about 600,000 centipoise. In some embodiments, apharmaceutical composition suitable for topical administrationsdescribed herein exhibits a viscosity of between about 100,000 and about500,000 centipoise. The viscosity is measured at a shear rate of 0.31s⁻¹ using a cone/plate viscometer (Brookfield DVII+Pro viscometer with aCP50 spindle at 0.08 rpm as a reference).

The compositions described herein are prepared by methods well known inthe art of pharmacy described in standard texts, such as Remington: TheScience and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995). The processes for preparing thenon-homogenous compositions described herein are performed withagitators, mechanical mixers, colloid mills homogenizers, ultrasonicdevices, microfluidizers and the like. In some embodiments thebubble-like regions of locally high ethanol concentration can be viewedwith the unaided eye. In other embodiments, the bubble-like regions oflocally high ethanol concentrations require the use of a microscope tovisualize.

Pharmaceutically Acceptable Salts and Prodrugs

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of thecorticosteriods described herein is intended to encompass any and allpharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar. In someembodiments, the corticosteroid salts are selected from acetate,diacetate, propionate, dipropionate, valerate, pivalate, diacetate, orbutyrate salts.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

In some embodiments, the corticosteroids described herein areadministered as phosphate prodrugs. In some embodiments, thecorticosteroids described herein are administered as sodium phosphateprodrugs. In some embodiments, the corticosteroids described herein areadministered as ester prodrugs. In some embodiments, the corticosteroidsdescribed herein are administered as acetyl, diacetyl, propanoate,dipropionate, pivalate, valerate, butyrate, butyl, furoate, orethoxycarbonyl ester prodrugs.

Excipients

Disclosed herein, in some embodiments, is a composition formulated as anon-homogenous ointment. In some embodiments, the ointment is aquaphore.In some embodiments, the ointment base is a hydrocarbon base selectedfrom white petrolatum, USP or white ointment, USP. In some embodiments,the ointment base is an absorption base selected from hydrophilicpetrolatum, USP or lanolin, USP. In some embodiments, the ointment baseis water-removable base, such as hydrophilic ointment, USP. In someembodiments, the ointment base is a water-soluble base, such aspolyethylene glycol ointment, NF.

Disclosed herein, in some embodiments, is a pharmaceutical compositionwherein the composition is a non-homogenous lotion or a non-homogenouscream. The hydrophobic component of a lotion or cream is derived from ananimal (e.g., lanolin, cod liver oil, and ambergris), plant (e.g.,safflower oil, castor oil, coconut oil, cottonseed oil, menhaden oil,palm kernel oil, palm oil, peanut oil, soybean oil, rapeseed oil,linseed oil, rice bran oil, pine oil, sesame oil, or sunflower seedoil), or petroleum (e.g., mineral oil, or petroleum jelly).

The compositions described herein are not foams.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition wherein the composition comprises a thickening agent. Insome embodiments, the composition disclosed herein further comprisesfrom about 0.1% to about 5%, more preferably from about 0.1% to about3%, and most preferably from about 0.25% to about 2%, of a thickeningagent.

In some embodiments, the excipient is selected from celluloses,cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose),guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid),silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan,paraffin, petrolatum, acacia (gum arabic), agar, aluminum magnesiumsilicate, sodium alginate, sodium stearate, bladderwrack, bentonite,carbomer, carrageenan, carbopol, xanthan, cellulose, microcrystallinecellulose (MCC), ceratonia, chondrus, dextrose, furcellaran, gelatin,ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin,mannitol, sorbitol, honey, maize starch, wheat starch, rice starch,potato starch, gelatin, sterculia gum, polyethylene glycol (e.g. PEG200-4500), gum tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose,ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, poly(hydroxyethylmethacrylate), oxypolygelatin, pectin, polygeline, povidone, propylenecarbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA),poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate),hydroxypropyl cellulose, hydroxypropylmethyl-cellulose (HPMC), sodiumcarboxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyrrolidone(PVP: povidone), or combinations thereof. In some embodiments, theexcipient is not a polysiloxane.

Disclosed herein, in some embodiments, is a pharmaceutical compositionwherein the composition comprises an emollient. Emollients include, butare not limited to, castor oil esters, cocoa butter esters, saffloweroil esters, cottonseed oil esters, corn oil esters, olive oil esters,cod liver oil esters, almond oil esters, avocado oil esters, palm oilesters, sesame oil esters, squalene esters, kikui oil esters, soybeanoil esters, acetylated monoglycerides, ethoxylated glycerylmonostearate, hexyl laurate, isohexyl laurate, isohexyl palmitate,isopropyl palmitate, methyl palmitate, decyloleate, isodecyl oleate,hexadecyl stearate decyl stearate, isopropyl isostearate, methylisostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyladipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, andcetyl lactate, oleyl myristate, oleyl stearate, and oleyl oleate,pelargonic acid, lauric acid, myristic acid, palmitic acid, stearicacid, isostearic acid, hydroxystearic acid, oleic acid, linoleic acid,ricinoleic acid, arachidic acid, behenic acid, erucic acid, laurylalcohol, myristyl alcohol, cetyl alcohol, hexadecyl alcohol, stearylalcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol,ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyl dodecanylalcohol, lanolin and lanolin derivatives, beeswax, spermaceti, myristylmyristate, stearyl stearate, carnauba wax, candelilla wax, lecithin, andcholesterol.

Disclosed herein, in some embodiments, is a pharmaceutical compositionwherein the composition comprises essential oils, fragrances,skin-conditioning agents, skin healing agents, skin protectants (e.g.,sunscreens, or ultraviolet light absorbers or scattering agents), skinsoothing agents, preservatives or combinations thereof.

Pharmaceutical compositions disclosed herein are formulated in anysuitable manner. Any suitable technique, carrier, and/or excipient iscontemplated for use with the non-homogenous compositions disclosedherein. For a summary of pharmaceutical topical formulations describedherein see Remington: The Science and Practice of Pharmacy, NineteenthEd (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Eighth Ed. (Lippincott Williams &Wilkins 2004), Muller, R. H. et al. Advanced Drug Delivery Reviews 59(2007) 522-530, which are herein incorporated by reference for suchdisclosures.

Device for the Treatment of Skin Diseases and Disorders

Another embodiment provides a device to be used by the patient prior totopical application of the therapeutic pharmaceutical compositiondisclosed herein wherein said device contains two reservoirs: a firstreservoir containing a first pharmaceutical composition comprisingethanol a second reservoir containing a second pharmaceuticalcomposition comprising a second active agent. Another embodimentprovides the device in which said first and second pharmaceuticalcompositions from said reservoirs are mixed by said device prior totopical application of the therapeutic pharmaceutical composition.Another embodiment provides the device in which said first and secondpharmaceutical compositions from said reservoirs are mixed by saiddevice prior to topical application of the therapeutic pharmaceuticalcomposition such that topical application of said therapeuticpharmaceutical composition does not irritate the skin. Anotherembodiment provides the device in which said first and secondpharmaceutical compositions from said reservoirs are mixed by saiddevice prior to topical application of the therapeutic pharmaceuticalcomposition such that topical application of said therapeuticpharmaceutical composition does not cause subjective irritation of theskin. Another embodiment provides the device in which said first andsecond pharmaceutical compositions from said reservoirs are mixed bysaid device prior to topical application of the therapeuticpharmaceutical composition such that topical application of saidtherapeutic pharmaceutical composition does not cause a stingingsensation.

Another embodiment provides the device wherein the therapeuticpharmaceutical composition is a non-homogeneous semisolid pharmaceuticalcomposition suitable for topical administration comprising from about 2%to no more than 59.9% ethanol by volume, at least one excipient, and asecond active ingredient. Another embodiment provides the device whereinthe therapeutic pharmaceutical composition is a non-homogenous semisoliddispersion. Another embodiment provides the device wherein thetherapeutic pharmaceutical composition is a non-homogenous semisolidemulsion. Another embodiment provides the device wherein the therapeuticpharmaceutical composition is a non-homogenous ointment or anon-homogenous cream. Another embodiment provides the device wherein thetherapeutic pharmaceutical composition is a non-homogenous ointment.Another embodiment provides the device wherein the therapeuticpharmaceutical composition is a non-homogenous cream.

Another embodiment provides the device wherein the therapeuticpharmaceutical composition is a non-homogeneous emulsion pharmaceuticalcomposition suitable for topical administration comprising from about 2%to no more than 59.9% ethanol by volume, at least one excipient, and asecond active ingredient. Another embodiment provides the device whereinthe therapeutic pharmaceutical composition is a dispersion. Anotherembodiment provides the device wherein the therapeutic pharmaceuticalcomposition is a non-homogenous lotion or a non-homogenous cream.Another embodiment provides the device wherein the therapeuticpharmaceutical composition is a non-homogenous lotion. Anotherembodiment provides the device wherein the therapeutic pharmaceuticalcomposition is a non-homogenous cream.

Another embodiment provides the device wherein the second activeingredient is selected from salicylic acid, glycolic acid, benzoylperoxide, sulfur, resorcinol, tretinoin, adapalene, tazarotene,clindamycin or erythromycin. Another embodiment provides the devicewherein the second active ingredient is selected from salicylic acid,glycolic acid, benzoyl peroxide, sulfur, resorcinol, tretinoin,adapalene, tazarotene, clindamycin, erythromycin, metronidazole, orazelaic acid. Another embodiment provides the device wherein the secondactive ingredient is selected from salicylic acid, terbenafine,econazole, miconazole, clotrimazole, butenafine, or tolnaftate.

Another embodiment provides the device wherein the second activeingredient is a corticosteroid selected from 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone diacetonide, and triamcinolone hexacetonide; and apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof.

Another embodiment provides the device wherein the second activeingredient is a corticosteroid selected from hydrocortisone, desonide,mometasone, betamethasone, fluticasone, fluocinolone, triamcinolone,triamcinolone acetonide, triamcinolone diacetonide, or clobetasol; and apharmaceutically acceptable salt thereof, or phosphate prodrug thereof,or ester prodrug thereof. Another embodiment provides the pharmaceuticalcomposition wherein the second active ingredient is a corticosteroidselected from hydrocortisone, desonide, mometasone, triamcinolone,triamcinolone acetonide, triamcinolone diacetonide, fluocinolone orfluticasone; and a pharmaceutically acceptable salt thereof, orphosphate prodrug thereof, or ester prodrug thereof. Another embodimentprovides the pharmaceutical composition wherein the second activeingredient is hydrocortisone or a pharmaceutically acceptable saltthereof, or phosphate prodrug thereof, or ester prodrug thereof. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is desonide, or a pharmaceutically acceptable saltthereof, or phosphate prodrug thereof, or ester prodrug thereof. Anotherembodiment provides the pharmaceutical composition wherein the secondactive ingredient is mometasone. Another embodiment provides thepharmaceutical composition wherein the second active ingredient isfluticasone, or a pharmaceutically acceptable salt thereof, or phosphateprodrug thereof, or ester prodrug thereof. Another embodiment providesthe pharmaceutical composition wherein the second active ingredient isfluocinolone. Another embodiment provides the pharmaceutical compositionwherein the second active ingredient is triamcinolone.

Another embodiment provides the device wherein the second activeingredient is a corticosteroid. Another embodiment provides the methodwherein the second active ingredient is selected from21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide, or a phosphate or ester prodrug thereof.

Another embodiment provides the device wherein the second activeingredient is selected from hydrocortisone, desonide, mometasone,betamethasone, fluticasone, triamcinolone, fluocinolone or clobetasol.Another embodiment provides the device wherein the second activeingredient is hydrocortisone, desonide, mometasone, fluocinolone,triamcinolone or fluticasone. Another embodiment provides the devicewherein the second active ingredient is hydrocortisone. Anotherembodiment provides the device wherein the second active ingredient isdesonide. Another embodiment provides the device wherein the secondactive ingredient is mometasone. Another embodiment provides the devicewherein the second active ingredient is fluticasone. Another embodimentprovides the device wherein the second active ingredient isfluocinolone. Another embodiment provides the device wherein the secondactive ingredient is triamcinolone.

Another embodiment provides a device for the preparation of anon-homogenous ethanol containing topical composition wherein the firstpharmaceutical composition is a gel, an emulsion, a dispersion, alotion, a cream, an ointment, or a solution. Another embodiment providesthe device wherein the first pharmaceutical composition containingethanol comprises from about 10% to about 20% ethanol. Anotherembodiment provides the device wherein the first pharmaceuticalcomposition containing ethanol comprises from about 20% to about 30%ethanol. Another embodiment provides the device wherein the firstpharmaceutical composition containing ethanol comprises from about 30%to about 40% ethanol. Another embodiment provides the device wherein thefirst pharmaceutical composition containing ethanol comprises from about40% to about 50% ethanol. Another embodiment provides the device whereinthe first pharmaceutical composition containing ethanol comprises fromabout 50% to about 60% ethanol. Another embodiment provides the devicewherein the first pharmaceutical composition containing ethanolcomprises from about 60% to about 70% ethanol. Another embodimentprovides the device wherein the first pharmaceutical compositioncontaining ethanol comprises from about 70% to about 80% ethanol.Another embodiment provides the device wherein the first pharmaceuticalcomposition containing ethanol comprises from about 80% to about 90%ethanol. Another embodiment provides the device wherein the firstpharmaceutical composition containing ethanol comprises from about 25%to about 35% ethanol. Another embodiment provides the device wherein thefirst pharmaceutical composition containing ethanol comprises from about35% to about 45% ethanol. Another embodiment provides the device whereinthe first pharmaceutical composition containing ethanol comprises fromabout 45% to about 55% ethanol. Another embodiment provides the devicewherein the first pharmaceutical composition containing ethanolcomprises from about 55% to about 65% ethanol.

Another embodiment provides a device for the preparation of anon-homogenous ethanol containing topical composition wherein saiddevice comprises means for mixing, agitating, shaking, stirring orblending a first pharmaceutical composition with a second pharmaceuticalcomposition. Another embodiment provides a device for the preparation ofa non-homogenous ethanol containing topical composition wherein saiddevice comprises containing means for a first pharmaceuticalcomposition, containing means for a second pharmaceutical composition,blending means to produce a non-homogenous composition, and dispensingmeans. Another embodiment provides the device wherein the blending meansis an enclosed chamber. Another embodiment provides the device whereinthe blending means is an enclosed chamber and the dispensing means is acontoured opening in the blending chamber.

Another embodiment provides the device wherein the therapeuticpharmaceutical composition is non-comedogenic.

EXAMPLES I. Preparation of Composition for Topical AdministrationExample 1-1 Preparation of an Ethanol Containing Gel

Ingredient Quantity ethanol 62.0 g water about 35.0 g Carbomer USP  0.5g NaOH (10%) about 2.5 g

A 100-g batch of ethanol gel formulation is prepared by suspending 0.5 gof carbomer USP in 62 g ethanol and about 30 g of water. The resultingmixture is agitated to ensure complete dissolution. The pH of thesolution is adjusted to pH 7 by the addition of about 2.5 g of 10% NaOHsolution and the resulting solution is brought to 100 g total mass bythe addition of about 5 g of water. The resulting material is packagedin a tube, bottle, or pump dispenser.

Example 1-2 General Procedure for the Preparation of an EthanolContaining Non-Homogenous Composition with Corticosteroid

Corticosteroid ointment and 62% ethanol gel were thoroughly mixedtogether. Volumes of the 62% ethanol and corticosteroid ointment variedand were dependent on the desired ratio of the two components (see Table1). The composition was immediately topically applied.

TABLE 1 Sample ratios of corticosteroid ointment to 62% ethanol gel andthe corresponding composition percent ethanol by volume Ratio ofcorticosteroid Volume of Composition ointment to corticosteroid Volumeof 62% percent ethanol ethanol gel ointment (mL) ethanol gel (mL) byvolume (%)  1:1 1.25 1.25 31  2:1 1.7 0.8 21  3:1 1.9 0.6 16  4:1 2.00.5 12  5:1 2.1 0.4 10  8:1 2.2 0.3 7 10:1 2.3 0.2 5

Example 1-3 Preparation of an Ethanol Containing Non-HomogenousComposition with Desonide 0.05%

For a 5:1 ratio of desonide 0.05% ointment to 62% ethanol gel: 0.4 mL of62% ethanol gel and desonide 0.05% ointment (2.1 mL) were thoroughlymixed together. The composition was immediately topically applied.

For a 10:1 ratio of desonide 0.05% ointment to 62% ethanol gel: 0.2 mLof 62% ethanol gel and desonide 0.05% ointment (2.3 mL) were thoroughlymixed together. The composition was immediately topically applied.

Example 1-4 Preparation of an Ethanol Containing Non-HomogenousComposition with Mometasone Furoate 0.1%

Compositions were prepared using the general method presented in Example1-2.

Example 1-5 Preparation of an Ethanol Containing Composition withTriamcinolone 0.1%

Compositions were prepared using the general method presented in Example1-2.

Example 1-6 Preparation of an Ethanol Containing Composition withFluocinolone 0.1%

Compositions were prepared using the general method presented in Example1-2.

Example 1-7 Preparation of Maintenance Non-Homogenous Lotion ContainingEthanol

Moisturizing lotion, cream or ointment and 62% ethanol gel werethoroughly mixed together. Volumes of the 62% ethanol gel andmoisturizing lotion, cream, or ointment varied and were dependent on thedesired ratio of the two components. The composition was immediatelytopically applied.

II. Treatment of Skin Diseases and Disorders Example 2-1 Treatment ofSecondarily Infected Dermatitis

Dermatitis is a common form of red, scaly, itchy patches whichfrequently is infected due to the patients scratching their itchy areas.Conventional treatment is based on use of topical steroid creams, andoral or topical antibiotics. Treatment often is only partly helpful andpatients often are reluctant to use oral antibiotics due to potentialside effects. Several patients have presented with secondarily infecteddermatitis and participated in the new course of treatment.

-   -   a. Man with hand dermatitis. Treatment with topical mometasone        cream and oral antibiotics and topical mupirocin provided        partial response over 3 weeks treatment. In an attempt to        achieve complete response the patient was treated with a        non-homogenous composition comprising mometasone (0.05%) and        ethanol (31%); no further oral antibiotics were administered.        The patient showed significant improvement in 3 days.    -   b. Man with extensive dermatitis over his trunk and limbs with        culture proven staphylococcus aureus. Treatment with a        non-homogenous composition comprising ethanol (31%) and        triamcinolone (0.05%) was far more effective than oral        antibiotic therapy (cephalexin) combined with triamcinolone        (0.1%) cream. Within 2 days the patient showed significant        improvement.    -   c. Woman with 20 years of hand dermatitis complicating        scleroderma (a form of skin tightening which compromises blood        flow). The patient reported 75% clearing of her condition within        3 days of starting a treatment with a non-homogenous composition        comprising ethanol (31%) and clobetasol (0.025%). The patient's        chronic condition had failed to respond to oral antibiotics,        topical antibiotics, topical cortisones including clobetasol        cream. This treatment with a non-homogenous composition        comprising ethanol (31%) and clobetasol (0.025%) worked when        clobetasol cream under plastic (glove occlusion) and cortisone        tape had failed.

Example 2-2 Treatment of Atopic Dermatitis (Eczema)

An 11 year old girl presented with recurrent persistent eczema onlypartly improved on the combined use of mometasone ointment and oralantibiotics. Within a week of starting a treatment with a non-homogenouscomposition comprising ethanol (31%) and mometasone (0.05%) thepatient's condition was 85% clear.

Example 2-3 Treatment of Facial Eczema

Twenty-six patients with facial eczema were treated for two weeks twicedaily with a non-homogenous ointment consisting of desonide 0.05%ointment mixed with 62% ethanol gel. The non-homogenous ointment wasused in fixed ratios ranging from 10:1 to 1:1 (desonide ointment/ethanolgel), or as part of a progressive ratio therapy in which the initialratio was 5:1 (desonide ointment/ethanol gel) and the ratio was changedevery 2 days to 3:1, then 2:1 and ending at 1:1. Each preparation wasprepared immediately prior to application. Results from all 26 patientsare displayed in Table 2. Results from nine patients who used fixedratios of desonide ointment/ethanol gel are displayed in Table 3.Results from 17 patients who underwent progressive ratio therapy aredisplayed in Table 4.

TABLE 2 Outcome of treatment using desonide/ethanol non-homogenouscomposition BID for 2 weeks in 26 patients with atopic dermatitis on theface: Number of patients Outcome of Treatment with this outcome worse 0same 1 25-50% better 1 51-74% better 1 75-99% better 12 100% better 11

TABLE 3 Outcome of treatment using fixed ratios of desonide/ ethanolnon-homogenous composition BID for 2 weeks in 9 patients with atopicdermatitis on the face: Number of patients with this outcome 1:1 4:1 5:110:1 Outcome of desonide/ desonide/ desonide/ desonide/ Treatment EtOHEtOH EtOH EtOH worse 0 0 0 0 same 0 0 0 0 25-50% better 0 0 0 0 51-74%better 0 0 0 0 75-99% better 1 1 6 0 100% better 0 0 0 1

TABLE 4 Outcome of treatment using progressive ratios of desonide/ethanol non-homogenous composition BID for 2 weeks in 17 patients withatopic dermatitis on the face: Number of patients Outcome of Treatmentwith this outcome worse 0 same 1 25-50% better 1 51-74% better 1 75-99%better 4 100% better 10

Based on the results from Table 2, the median improvement score was 87%.The mean improvement score was 86%. 88% of the patients achieved 75% orgreater improvement compared to pretreatment. Treatment was welltolerated. None of the patients had to stop treatment due to irritation.Patients using compositions of different ratios of the desonide ointmentand ethanol gel, ranging from 10:1 (desonide ointment/ethanol gel) to1:1, achieved comparable results in this study.

Example 2-4 Treatment of Atopic Dermatitis on the Trunk and/or Limbs

Forty-eight patients with trunk and/or limb eczema were treated for twoweeks twice daily with a non-homogenous ointment consisting ofmometasone furoate 0.1% ointment mixed with 62% ethanol gel. Thenon-homogenous ointment was used in fixed ratios ranging from 10:1(mometasone furoate ointment/ethanol gel) to 1:1 or as part of aprogressive ratio therapy in which the initial ratio was 5:1 mometasoneointment/ethanol gel and the ratio was changed every 2 days to 3:1, then2:1 and ending at 1:1. Each preparation was prepared immediately priorto application. Results from all 48 patients are displayed in Table 5.Results from 13 patients who used fixed ratios of desonideointment/ethanol gel are displayed in Table 6. Results from 35 patientswho underwent progressive ratio therapy are displayed in Table 7.

TABLE 5 Outcome of treatment using mometasone/ethanol non-homogenouscomposition BID for 2 weeks in 48 patients with atopic dermatitis on thetrunk and/or limbs: Number of patients Outcome of Treatment with thisoutcome worse 0 same 1 25-50% better 0 51-74% better 0 75-99% better 28100% better 19

TABLE 6 Outcome of treatment using fixed ratios of mometasone/ ethanolnon-homogenous composition BID for 2 weeks in 13 patients with atopicdermatitis on the trunk and/or limbs: Number of patients with thisoutcome 1:1 4:1 5:1 10:1 Outcome of mometasone/ mometasone/ mometasone/mometasone/ Treatment EtOH EtOH EtOH EtOH worse 0 0 0 0 same 0 0 0 025-50% better 0 0 0 0 51-74% better 0 0 0 0 75-99% better 1 2 4 1 100%better 0 1 4 0

TABLE 7 Outcome of treatment using progressive ratios of mometasone/ethanol non-homogenous composition BID for 2 weeks in 35 patients withatopic dermatitison the trunk and/or limbs: Number of patients Outcomeof Treatment with this outcome worse 0 same 1 25-50% better 0 51-74%better 0 75-99% better 20 100% better 14

Based on the data from Table 5, the median improvement score was 87%.The mean improvement score was 90%. 98% of the patients achieved 75% orgreater improvement compared to pretreatment. Treatment was welltolerated. None of the patients had to stop treatment due to irritation.Patients using compositions of different ratios of the mometasoneointment and ethanol gel, ranging from 10:1 (mometasone ointment/ethanolgel) to 1:1, achieved comparable results in this study.

Example 2-5 Summary of Corticosteroid-Ethanol Formulations Evaluated forthe Treatment of Eczema

Table 8 provides a summary of the corticosteroid formulations evaluatedin the clinic for the treatment of eczema using the methods describedherein. In all cases the eczema improved at least 75% compared topretreatment, and the treatment was well-tolerated.

TABLE 8 Ratio Structural Corticosteroid Concen- Class of CorticosteroidTopical mixed with tration Corticosteroid tested Ethanol gel Ethanol gelClass A Hydrocortisone 10:1 and 5:1 70% Hydrocortisone 2.5% ointmentType Hydrocortisone 10:1 and 5:1 62% 1% OTC cream Class B Amcinonide0.1% 10:1 and 5:1 70% Triamcinalone cream Acetonide (Cyclocort ®) TypeAmcinonide 0.1% 10:1 and 5:1 70% ointment (Cyclocort ®) Desonide 0.05% 4:1 and 1:1 62% cream Desonide 0.05% 10:1, 5:1, 4:1, 2:1, 1:1 62%ointment Fluocinolone 10:1 and 1:1 62% acetonide 0.025% ointment(Synalar ®) Fluocinonide 10:1 and 1:1 62% 0.05% cream (Lidex ®)Fluocinonide 10:1 and 1:1 62% 0.05% ointment (Lidex ®) Triamcinolone 1:162% acetonide 0.1% cream Triamcinolone  5:1 and 1:1 62% acetonide 0.1%ointment Triamcinalone 10:1 and 5:1 62% diacetate 0.1% ointmentHalocinonide 10:1 and 5:1 62% 0.1% ointment (Halog ®) Halobetasol 10:1and 5:1 62% propionate 0.05% ung (Ultravate ®) Class C Clocortolone 1:162% Betamethasone pivalate Type 0.1% cream (Cloderm ®) Desoximetasone10:1 and 5:1 70% 0.25% ointment Class D1 Alclometasone 10:1 and 5:1 70%Betamethasone dipropionate Dipropionate 0.05% Type (Aclovate ®) OintmentBetamethasone 10:1 and 5:1 70% dipropionate 0.05% ointment (Diprolene ®)Betamethasone 10:1 and 5:1 62% dipropionate augmented 0.05% ointmentBetamethasone 10:1 and 5:1 62% valerate 0.1% ointment Fluticasone 10:1and 5:1 62% propionate 0.005% cream (Cutivate ®) Fluticasone 10:1 and5:1 62% propionate 0.005% ointment (Cutivate ®) Mometasone 10:1, 5:1,4:1, 2:1, 1:1 62% 0.1% ointment Diflorasone 10:1 and 5:1 70% diacetate0.05% ointment (Psorcon ®) Clobetasol  4:1 and 1:1 62% propionate 0.05%ointment (Temovate ®) Clobetasol 5:1 62% propionate 0.05% cream(Temovate ®) Class D2 Hydrocortisone 10:1 and 5:1 62% Methyl- Butyrateprednisolone 0.1% ointment Aceponate (Locoid ®) Type Hydrocortisone10:1  62% Butyrate 0.1% cream (Locoid ®) Hydrocortisone 10:1 and 5:1 70%valerate 0.2% ointment Prednicarbate 10:1 and 5:1 62% 0.1% creamUncertain fluradrenolide 10:1 and 5:1 62% structural 0.05% cream class(potency class 5)

Example 2-6 Summary of Outcomes of Various Combinations of TopicalCorticosteroids and Ethanol for Treating Eczema (ArrangedAlphabetically)

Table 9 provides a summary of outcomes using the methods describedherein of various combinations of topical corticosteroids and ethanol.In all cases the treatment was well-tolerated.

TABLE 9 Ratio by Amount of Net CS Initial CS volume of reduction inconcentration % concentration topical CS CS in the non- Number patientspresent in and 62% concentration homogenous of achieving Topical CStopical ethanol gel in in final mixture as patients treatment testedpreparation the mixture* mixture administered treated success**Alclometasone 0.050%  5:1 ⅙ 0.042% 1 100% dipropionate Ung (Aclovate ®)Amcinonide Cr 0.100%  5:1 ⅙ 0.083% 1 100% (Cyclocort ®) Amcinonide Ung0.100%  5:1 ⅙ 0.083% 1 100% (Cyclocort ®) Betamethasone 0.050%  5:1 ⅙0.042% 1 100% propionate Aug Ung (Diprolene ®) Betamethasone 0.050%  5:1⅙ 0.042% 1 100% propionate Ung (Diprolene ®) Betamethasone 0.100%  5:1 ⅙0.083% 1 100% valerate Ung (Valisone ®) Clobetasol 0.050%  5:1 ⅙ 0.042%1 100% propionate Cr (Temovate ®) Clobetasol 0.050%  1:1 ½ 0.025% 2 100%propionate Ung (Temovate ®) Clobetasol 0.050%  4:1 ⅕ 0.040% 1 100%propionate Ung (Temovate ®) Clocortolone 0.100%  1:1 ½ 0.050% 1 100%pivalate Cr (Cloderm ®) Desonide Cr 0.050%  4:1 ⅕ 0.040% 1 100% DesonideCr 0.050%  2:1 ⅓ 0.033% 1 100% Desonide Cr 0.050%  1:1 ½ 0.025% 2 100%Desonide Ung 0.050%  1:1 ½ 0.025% 28 96% Desonide Ung 0.050% 10:1 1/110.046% 6 100% Desonide Ung 0.050%  2:1 ⅓ 0.033% 2 100% Desonide Ung0.050%  4:1 ⅕ 0.040% 2 100% Desonide Ung 0.050%  5:1 ⅙ 0.042% 18 94%Desoximetasone 0.250%  5:1 ⅙  0.21% 3 100% Ung (Topicort ®) Diflorasone0.050%  5:1 ⅙ 0.042% 1 100% diacetate Ung (Psorcon ®) Fluocinolone0.025%  5:1 ⅙ 0.021% 2 100% acetonide Ung (Synalar ®) Fluocinonide Cr0.050%  1:1 ½ 0.025% 4 100% (Lidex ®) Fluocinonide 0.050%  1:1 ½ 0.025%2 100% Ung (Lidex ®) Flurandrenolide 0.050%  5:1 ⅙ 0.042% 2 100% Cr(Cordran SP ®) Fluticasone 0.005%  5:1 ⅙ 0.004% 3 100% propionate Ung(Cutivate ®) Halobetasol 0.050%  5:1 ⅙ 0.042% 1 100% propionate Cr(Ultravate ®) Halocinonide Cr 0.100%  1:1 ½ 0.050% 1 100% (Halog ®)Hydrocortisone 1.000%  5:1 ⅙ 0.833% 1 100% Cr OTC Hydrocortisone  2.5% 5:1 ⅙ 2.083% 1 100% Ung Hydrocortisone 0.100%  5:1 ⅙ 0.083% 1 100%butyrate Cr (Locoid ®) Hydrocortisone 0.100%  5:1 ⅙ 0.083% 2 100%butyrate Ung (Locoid ®) Hydrocortisone 0.200%  5:1 ⅙ 0.167% 1 100%valerate Ung (Westcort ®) Mometasone Cr 0.100%  1:1 ½ 0.050% 2 100%(Elocon ®) Mometasone Cr 0.100%  2:1 ⅓ 0.067% 1 100% (Elocon ®)Mometasone Cr 0.100%  5:1 ⅙ 0.083% 1 100% (Elocon ®) Mometasone 0.100% 5:1 ⅙ 0.083% 14 93% Ung (Elocon ®) Mometasone 0.100%  1:1 ½ 0.050% 2796% Ung (Elocon ®) Mometasone 0.100% 10:1 1/11 0.091% 5 77% Ung(Elocon ®) Mometasone 0.100%  2:1 ⅓ 0.067% 5 100% Ung (Elocon ®)Mometasone 0.100%  4:1 ⅕ 0.080% 6 100% Ung (Elocon ®) Mometasone 0.100% 3:1 ¼ 0.075% 2 100% Ung (Elocon ®) Prednicarbate 0.100%  5:1 ⅙ 0.083% 1100% Ung (Dermatop ®) Triamcinolone 0.100%  1:1 ½ 0.050% 1 100%acetonide Cr (Kenalog ®) Triamcinolone acetonide Ung (Kenalog ®) 0.100% 1:1 ½ 0.050% 1 100% Triamcinolone acetonide Ung (Kenalog ® ) 0.100% 5:1 ⅙ 0.083% 2 100% Triamcinolone 0.100%  5:1 ⅙ 0.083% 1 100% diacetateUng (Aristocort ®) CS = corticosteroid *The ratio is the relative amountof the topical corticosteroid to be combined with the ethanol gel toform the mixture. For example: 5 to 1 ratio means 5 parts corticosteroidto 1 part ethanol gel. This results in a final corticosteroidconcentration which is ⅚ of the initial concentration or a 17% drop ininitial corticosteroid concentration. **Success is defined as 75% orgreater reduction in amount of eczema rash compared to pretreatment.

Example 2-7 Comparison of the Results of Clinical Trials for TreatingEczema in Children with Corticosteroid/Ethanol Non-HomogenousComposition Versus Published Results for Using Conventional Treatment

1) Topical Mometasone/Ethanol Prototype Compared to “Bleach Baths” inTreating Children with Eczema.

A recent study (Huang J T, Abrams M, Tlougan B, Rademaker A, Paller A S.Treatment of staphylococcus aureus colonization in atopic dermatitisdecreases disease severity. Pediatrics May 2009; 123(5): 808-814)evaluated a new method for treating eczema employing “bleach baths” totopical corticosteroid treatment as a means to suppress thestaphylococcal population on the skin. This bleach bath-topicalcorticosteroid treatment resulted in a mean improvement of 40% in 1month of use. These results were inferior to twice daily treatment ofprototype non-homogenous ointment consisting of mometasone furoate 0.1%ointment mixed with 62% ethanol gel in fixed or progressive ratios,which resulted in a mean improvement of 90% in two weeks (data presentedin Table 5).

2) Topical Desonide/Ethanol Non-Homogenous Composition Compared toConventional Desonide Formulations in Treating Children with Eczema.

The use of commercially available desonide formulations in treatingchildren with eczema has been reported in the literature. Desonide 0.05%hydrogel and desonide 0.05% ointment provided 25% and 34% success,respectively, after 2 weeks of therapy and 25% and 52% success,respectively, after 3-6 weeks of therapy (Trookman N S, Rizer R L.Randomized Controlled Trial of Desonide Hydrogel 0.05% versus DesonideOintment 0.05% in the Treatment of Mild-to-moderate Atopic Dermatitis. JClin Aesthet Dermatol. November 2011; 4(11): 34-38). Another studyshowed that desonide 0.05% hydrogel and its hydrogel vehicle provided19% and 3% success, respectively, after 2 weeks of therapy and 39% and11% success, respectively, after 3-6 weeks of therapy (Hebert A A,Cook-Bolden F E, Basu S, Calvarese B, Trancik R J. Safety and efficacyof desonide hydrogel 0.05% in pediatric subjects with atopic dermatitis.J Drugs Dermatol. February 2007; 6(2):175-81). In these two studies, thedesonide hydrogel contains propylene glycol in its vehicle and thedesonide ointment contains no alcohol. In sharp contrast, prototypenon-homogenous ointment consisting of a mixture of desonide/ethanol infixed or progressive ratios led to 88% success after two weeks of twicedaily treatment (data shown in Table 2). The prototype non-homogenousointment provided better results in a shorter period of time. In allstudies, success was defined as the percentage of patients that achieved75% or better improvement compared to baseline.

3) Topical Mometasone/Ethanol Non-Homogenous Composition Compared toConventional Mometasone Cream in Treating Children with Eczema.

The use of commercially available mometasone formulations for thetreatment of children with eczema has been reported in the literature.One study found that mometasone 0.1% cream provided 50% success after 3weeks of therapy (Rafanelli A, Rafanelli S, Stanganelli I, et. al.Mometasone furoate in the treatment of atopic dermatitis in children. J.Eur. Acad. Dermatol. Venereol. 1993; 2(3):225-230). Another study foundthat mometasone 0.1% cream led to 63% success after 3 weeks of therapy(Vernon H J, Lane A T, Weston W. Comparison of mometasone furoate 0.1%cream and hydrocortisone 1.0% cream in the treatment of childhood atopicdermatitis. J. Am. Acad. Dermatol. April 1991; 24:603-7). A third studyreported overall results similar to the other two studies (Lebwohl M,Lane A T, Berman B, et. al. Efficacy and safety of 0.1% mometasonefuroate cream versus 0.2% hydrocortisone valerate cream in pediatricpatients with atopic dermatitis un-responsive to topical hydrocortisonetreatment. Proceedings of the 55^(th) Annual Meeting of the AmericanAcademy of Dermatology Mar. 21-26, 1997; abstract number P-43). In allcases, the mometasone 0.1% cream included propylene glycol stearate (55%monoester) in its vehicle. Use of the prototype non-homogenous ointmentconsisting of a mixture of mometasone/ethanol in fixed or progressiveratios provided 98% success after only two weeks of twice dailytreatment (data in Table 5). In all studies, success was defined aspercentage of patients achieving 75% or better improvement compared tobaseline.

Example 2-8 Clinical Trial of Moisturizer/Ethanol Non-HomogenousComposition in Preventing Recurrence of Eczema

Demographics: 7 patients with chronic recurrent eczema entered thetrial. Prior to starting the trial all had cleared their eczema rashusing rash treatment prototype topical therapy. All had a past historyof conventional moisturizers failing to prevent recurrence of eczemawithin 10 days of stopping prior rash therapy.

Protocol: All used maintenance non-homogenous lotion twice a day.

Materials: The maintenance non-homogenous lotion was Cetaphil™moisturizing lotion mixed in a ratio of 1:1 with 62% ethanol gelimmediately before application.

Duration of follow-up:

-   -   a. 1 month: 2 patients    -   b. 1.5 months: 1 patient    -   c. 2 months: 2 patients    -   d. 6 months: 1 patient    -   e. 7 months: 1 patient

Outcome of Protocol Treatment: 6 of the 7 patients reported they stayedentirely clear while on consistent use maintenance therapy. One patientreported when the weather got very cold and dry, the rash recurreddespite the maintenance therapy.

Conclusion

The maintenance prototype was strikingly effective in maintainingpatients rash-free.

Example 2-9 Two Case Studies Demonstrating Killing or Inhibition of S.aureus Growth Using Corticosteroid/Ethanol Non-Homogenous Compositions

Case 1: A 26-year old man with eczema on the hand was treated twicedaily for three days with a mixture of triamcinolone 0.1% ointment in a5:1 ratio with 62% ethanol gel. The pre-treatment bacterial culture fromthe eczematous rash reported growth of S. aureus. The post-treatmentbacterial culture performed after three days of treatment showed no S.aureus present.

Case 2: A 92-year old man with eczema on the hand was treated twicedaily for seven days with a mixture of fluocinolone 0.1% ointment in a1:1 ratio with 62% ethanol gel. The pre-treatment bacterial culture fromthe eczematous rash reported growth of S. aureus. The post-treatmentbacterial culture performed after seven days of treatment showed no S.aureus present.

Example 2-10 Non-Stinging Test Using Superficial Skin Abrasion Model

In a study with 20 subjects, this test is performed on a total of 6sites on each subject: three test sites on each arm. Tape is used tosequentially strip the skin until the glistening layer is visible. Thetest materials include a positive stinging control (70% ethanolsolution), a negative stinging control (formulation vehicle withoutethanol) and the novel formulation with ethanol (with or without asecond active agent). Each material is applied to a single site on eachforearm to allow for a separate determination of response consistency.Each material is applied for 15 seconds to each site. Each subjectreports the intensity of the stinging/burning sensation on a 0-4 pointscale. The outcome of the study is determined by comparing the scores ofall the sites.

Example 2-11 Treatment of Tinea Versicolor

Tinea versicolor is a rash in humans known to be caused by two speciesof malassezia: malassezia globosa and malassezia furfur.

The patient was a 39 year old man with a two-year history of extensivetan moderately scaling patches symmetrically on the chest and back.Condition failed to respond to a month of conventional treatment withzinc pyrithione lotion. The diagnosis was confirmed by a KOH microscopicexamination of a specimen from the back rash showing very large numbersof short fat hyphae and round yeasts.

Treatment of once daily application of 70% ethanol gel to affected areasfor two weeks was begun. The patient reported that the treatment waswell tolerated and comfortable to perform.

The course of treatment resulted in the back patches post-treatmentshowing 10% of the pretreatment scaling. KOH microscopic examination ofthe rash done post treatment showed complete absence of hyphae and roundyeast. The chest patches post treatment had 25% of pretreatment scaling.The KOH microscopic examination of the specimen post treatment showedrare short fat hyphae and no round yeasts.

Conclusions: Ethanol killed malassezia genus organisms in this in vivotherapeutic trial. The patient demonstrated improvement in the rash bothas measured by clinical examination and microscopic assessment.

Example 2-12 Treatment of Seborrheic Dermatitis

The patient was a 79-year old man with a prolonged, multi-year historyof facial seborrheic dermatitis which failed to respond adequately toeither a low potency prescription corticosteroid cream (hydrocortisonevalerate 0.2%), or to a mid-potency corticosteroid cream (mometasone0.1%) in combination with an anti-fungal cream (ketoconazole cream). Ina trial of the compositions described herein, he applied twice a day for6 days a non-homogenous 10:1 mixture of hydrocortisone butyrate cream0.1% (10 parts) and 62% ethanol gel (1 part). This course of therapyresulted in 100% clearing of the facial areas treated and was welltolerated. The patient reported he had never cleared this much, or thisfast, from any of the prior therapies.

Example 2-13 Treatment of Persistent Eczema

A chemical matrix for the treatment of eczema using triamcinaloneacetonide and ethanol was prepared as described in Example 1-3 using thefollowing ingredients:

2.5 ml of triamcinalone acetonide cream 0.1%;

2.5 ml of Aquaphore; and

1 ml of 62% ethanol gel.

The final concentration of active ingredients in this new chemicalmatrix are: triamcinalone acetonide 0.042%, and ethanol 10.3%.

A 64-year-old woman presented with extensive, extremely itchy, crustedeczema on the trunk and legs and such a condition had existed for over ayear. The condition persisted despite treatment with triamcinaloneacetonide cream 0.1% used daily for more than 9 months. No improvementwas observed when she covered the areas treated with the triamcinalonecream for 8 hours with wet pajamas. Treatment was begun using the sametriamcinalone acetonide 0.1% cream but now reformulated into thechemical matrix described above. The triamcinalone acetonide and ethanolmatrix was applied twice daily without any wet covering. The patientreported within 24 hours of treatment the itching was greatly reduced.When examined after 1 week of treatment, the former rash was 95%resolved.

Example 2-14 Treatment of Persistent Pediatric Eczema

A chemical matrix for the treatment of eczema using desonide and ethanolwas prepared as described in Example 1-3 using the followingingredients:

2.5 ml of desonide ointment 0.05%;

2.5 ml of Aquaphore; and

1 ml of 62% ethanol gel.

The final concentration of active ingredients in this new chemicalmatrix are: desonide 0.021%, and ethanol 10.3%.

An 18-month-old child presented with extensive, extremely itchy, crustedeczema on the face, trunk, arms, and legs persisting for several months,worsening in the preceding 10 days. Treatment with moisturizing creamsand 1% hydrocortisone cream did not resolve the rash. Treatment wasbegun using the desonide and ethanol matrix described above. Thedesonide and ethanol matrix was applied twice daily. The parentsreported the rash was almost entirely resolved at 4 days of treatment.

While preferred embodiments of the present inventions have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the inventions. It should beunderstood that various alternatives to the embodiments of the inventiondescribed herein may be employed in practicing the invention. It isintended that the following claims define the scope of the inventionsand that methods and structures within the scope of these claims andtheir equivalents be covered thereby.

What is claimed is:
 1. A chemical matrix comprising from about 2% toabout 30% of an alcohol by volume, a corticosteroid and at least oneexcipient, wherein the chemical matrix is an ointment suitable fortopical non-systemic administration, the alcohol is primarily dispersedinto the chemical matrix in the form of microbubbles, and the alcohol isselected from ethanol, isopropanol, or n-propanol.
 2. The chemicalmatrix of claim 1, wherein the alcohol is ethanol.
 3. The chemicalmatrix of claim 1, wherein the ointment is selected from whitepetrolatum USP, white ointment USP, hydrophilic petrolatum USP, orhydrophilic ointment USP.
 4. The chemical matrix of claim 1, wherein thecorticosteroid is selected from desonide, or mometasone.
 5. The chemicalmatrix of claim 2, wherein the chemical matrix comprises from about 2%to about 10% ethanol by volume.
 6. The chemical matrix of claim 2,wherein the chemical matrix comprises from about 10% to about 20%ethanol by volume.
 7. The chemical matrix of claim 2, wherein thechemical matrix comprises from about 20% to about 30% ethanol by volume.8. The chemical matrix of claim 5, wherein the corticosteroid isselected from desonide, or mometasone.
 9. The chemical matrix of claim6, wherein the corticosteroid is selected from desonide, or mometasone.10. The chemical matrix of claim 7, wherein the corticosteroid isselected from desonide, or mometasone.
 11. The chemical matrix of claim4, wherein the corticosteroid comprises from about 0.1% (w/w) to about0.0001% (w/w) of the chemical matrix.
 12. The chemical matrix of claim8, wherein the corticosteroid comprises from about 0.1% (w/w) to about0.0001% (w/w) of the chemical matrix.
 13. The chemical matrix of claim9, wherein the corticosteroid comprises from about 0.1% (w/w) to about0.0001% (w/w) of the chemical matrix.
 14. The chemical matrix of claim10, wherein the corticosteroid comprises from about 0.1% (w/w) to about0.0001% (w/w) of the chemical matrix.
 15. A method of treating a skindisease or disorder in an individual in need thereof comprising topicalapplication to the individual of a chemical matrix comprising from about2% to about 30% of an alcohol by volume, a corticosteroid and at leastone excipient, wherein the chemical matrix is an ointment suitable fortopical non-systemic administration, the alcohol is primarily dispersedinto the chemical matrix in the form of microbubbles, and the alcohol isselected from ethanol, isopropanol, or n-propanol.
 16. The method ofclaim 15, wherein the alcohol is ethanol.
 17. The method of claim 15,wherein the ointment is selected from white petrolatum USP, whiteointment USP, hydrophilic petrolatum USP, or hydrophilic ointment USP.18. The method of claim 15, wherein the corticosteroid is selected fromdesonide, or mometasone.
 19. The method of claim 16, wherein thechemical matrix comprises from about 2% to about 10% ethanol by volume.20. The method of claim 16, wherein the chemical matrix comprises fromabout 10% to about 20% ethanol by volume.
 21. The method of claim 16,wherein the chemical matrix comprises from about 20% to about 30%ethanol by volume.
 22. The method of claim 19, wherein thecorticosteroid is selected from desonide, or mometasone.
 23. The methodof claim 20, wherein the corticosteroid is selected from desonide, ormometasone.
 24. The method of claim 21, wherein the corticosteroid isselected from desonide, or mometasone.
 25. The method of claim 15,wherein the skin disease or disorder is dermatitis.
 26. The method ofclaim 15, wherein the skin disease or disorder is eczema.
 27. The methodof claim 15, wherein the skin disease or disorder is atopic dermatitis.